Comprehensive Physiology Wiley Online Library
For Librarians For Authors Editors About

Role of Perivascular Adipose Tissue in Health and Disease

Maria S. Fernández‐Alfonso, Beatriz Somoza, Dmitry Tsvetkov, Artur Kuczmanski, Mick Dashwood, Marta Gil‐Ortega

10.1002/cphy.c170004

Source: Volume 8, Issue 1, January 2018

Published online: December 2017

Full Article on Wiley Online Library



ABSTRACT

Perivascular adipose tissue (PVAT) is cushion of fat tissue surrounding blood vessels, which is phenotypically different from other adipose tissue depots. PVAT is composed of adipocytes and stromal vascular fraction, constituted by different populations of immune cells, endothelial cells, and adipose‐derived stromal cells. It expresses and releases an important number of vasoactive factors with paracrine effects on vascular structure and function. In healthy individuals, these factors elicit a net anticontractile and anti‐inflammatory paracrine effect aimed at meeting hemodynamic and metabolic demands of specific organs and regions of the body. Pathophysiological situations, such as obesity, diabetes or hypertension, induce changes in its amount and in the expression pattern of vasoactive factors leading to a PVAT dysfunction in which the beneficial paracrine influence of PVAT is shifted to a pro‐oxidant, proinflammatory, contractile, and trophic environment leading to functional and structural cardiovascular alterations and cardiovascular disease. Many different PVATs surrounding a variety of blood vessels have been described and exhibit regional differences. Both protective and deleterious influence of PVAT differs regionally depending on the specific vascular bed contributing to variations in the susceptibility of arteries and veins to vascular disease. PVAT therefore, might represent a novel target for pharmacological intervention in cardiovascular disease. © 2018 American Physiological Society. Compr Physiol 8:23‐59, 2018.

Comprehensive Physiology offers downloadable PowerPoint presentations of figures for non-profit, educational use, provided the content is not modified and full credit is given to the author and publication.

Download a PowerPoint presentation of all images


Figure 1. Figure 1. Diagram of histological and ultrastructural cell composition of perivascular adipose tissue. Perivascular adipose tissue (PVAT) differs from other adipose depots in cell composition. PVAT adipocytes (in yellow) constitute the main cellular component of PVAT. In addition, PVAT contains other cell types like preadipocytes, fibroblasts, endothelial cells (in red) and immune cells (macrophages in blue and T cells in black). Those cells constitute the stromal vascular fraction of PVAT. PVAT extracellular matrix is formed by collagen and elastic fibers (in green). PVAT is innervated by the sympathetic nervous system and harbors adrenergic nerve endings.
Figure 2. Figure 2. Perivascular adipose tissue release vasoactive factors thus modulating vascular function and structure. Perivascular adipose tissue (PVAT) surrounding the vascular wall of conductance, resistance arteries and microvessels releases vasoactive factors that can produce either vascular relaxation (perivascular relaxing factors, PVRFs) or vascular contraction (perivascular contractile factors, PVCFs). The direction of the effect on vascular tone, arterial growth and remodeling, extracellular matrix turnover or arterial stiffness depends on the balance between PVRFs and PVCFs.
Figure 3. Figure 3. Anticontractile effect of perivascular adipose tissue in mesenteric artery rings. (A) Representative experiment of vascular function determined by wire myography in isolated mesenteric arteries from wild‐type (C57BL/6) mice with (+) and without (‐) perivascular adipose tissue (PVAT) in response to KCl (6 × 10−2 M) and phenylephrine (PE, 10−8‐10−4 M). In presence of PVAT, contractions to PE but not KCl are lower compared with the mesenteric ring deprived of PVAT. The net beneficial anticontractile effect of PVAT on PE‐contraction is represented in yellow. Adapted, with permission, from (349). (B) Representative concentration‐response curve to PE in mesenteric artery rings (+) PVAT/(−) PVAT, isolated from wild‐type (C57BL/6) mice. Contractions are expressed as the percentage of contraction induced by 6 × 10−2 M KCl. The area between the curves, illustrated in yellow, represents the anti‐contractile effect of PVAT and is reflected by a shifting to the right of the concentration‐response curve to PE. The contraction to PE (10−8‐10−4 M) is significantly higher in arteries without PVAT. *, P < 0.05 compared to (+) PVAT. Adapted, with permission, from (349). (C) Representative concentration‐response curve to PE in mesenteric arteries isolated from PI3Kγ and PI3Kδ deficient mice (Pik3cg–/–/Pik3cd–/–). PI3K (isoforms) are implicated in the regulation of arterial contraction via α1‐adrenergic receptors (agonist PE). Regulation of arterial tone by PVAT occurs without the PI3Kγ and PI3Kδ involvement. The area between the curves, illustrated in blue, represents the anti‐contractile effect of PVAT. The contractile response to PE (10−8‐10−4 M) is significantly higher in arteries without PVAT. *, P < 0.05 compared to (+) PVAT. Adapted, with permission, from (348).
Figure 4. Figure 4. Mechanisms of arterial tone reduction induced by perivascular relaxing factors. Perivascular relaxing factors induce arterial vasodilation through diverse endothelium‐dependent and endothelium‐independent mechanisms. Adipocyte‐derived relaxing factor (ADRF) and palmitic acid methyl ester (PAME) induce vasodilation by opening voltage‐dependent potassium (Kv) channels in vascular smooth muscle cells (VSMC). Hydrogen sulfide (H2S) open both voltage gated Kv7 (KCNQ) and ATP‐dependent K+ (KATP) channels in VSMC. Free fatty acids (FFAs), nitric oxide (NO), and hydrogen peroxide (H2O2) open calcium‐activated potassium (BKCa) channels in VSMC. K+ channels opening leads to an increase in intracellular K+ concentrations thus accounting for VSMCs’ hyperpolarization followed by arterial relaxation. Adiponectin and leptin induce a direct vasodilation through both K+ channel opening in VSMC and NO secretion, due to protein kinase B (Akt) phosphorylation followed by endothelial nitric oxide synthase (eNOS) phosphorylation at Ser1177. Leptin also increases endothelium‐derived hyperpolarization factor (EDHF) levels. Omentin activates adenosine monophosphate‐activated protein kinase AMP‐(AMPK) signalling in endothelial cells (EC) and stimulate eNOS phosphorylation at Ser1177 thus increasing NO availability.
Figure 5. Figure 5. Mechanisms of putative PVRFs’ regulation of vascular tone. Effects of exercise on skeletal muscle are mediated by the transcriptional peroxisome proliferator‐activated receptor gamma coactivator 1‐α (PGC1α). PGC1α stimulates an increase in the expression of fibronectin type III domain‐containing protein 5 (FNDC5). The FNDC5 gene encodes a type I membrane protein known as irisin. Perivascular adipose tissue (PVAT)‐derived irisin increases uncoupling protein 1 (UCP‐1) and cell death activator CIDE‐A (Cidea) expression, thus enhancing browning of PVAT. Those effects are accompanied by the upregulation of the heme oxygenase‐1 (HO‐1) followed by a reduction in pro‐inflammatory cytokines (tumor necrosis factor alpha, TNF‐α) and CD3 and oxidative stress (superoxide anion, O2 −) as well as an increase in adiponectin levels. The latter activates endothelial adenosine monophosphate‐activated protein kinase AMP (AMPK) that induces endothelial nitric oxide synthase (eNOS) phosphorylation, thus accounting for nitric oxide (NO) release and vasorelaxation.
Figure 6. Figure 6. Physiological and pathological role of the renin‐angiotensin system in periaortic adipose tissue. All components of the renin‐angiotensin system (RAS) are expressed or synthesized in perivascular adipose tissue (PVAT) of rat aorta. The physiological role of PVAT‐derived RAS peptides seems to be dual: (i) Angiotensin II (Ang II), when bound to AT1 receptors, increases adrenergic activity, thus enhancing noradrenaline (NA) levels and VSMCs’ contractions; (ii) Angiotensin (1,2,3,4,5,6,7) induces relaxation of VSMCs through the endothelial Mas receptor. However, in obesity, AT1 activation by abdominal periaortic adipose tissue (aPAAT)‐derived Ang II increases inflammation in aPAAT, favoring the entry of periadventitial leukocytes into the vascular wall together with an increase in the expression of proinflammatory cytokines (tumor necrosis factor alpha, TNF‐α, interleukin 6, IL‐6) and matrix metalloproteinase‐2 (MMP‐2) as well as an enhancement of aldosterone levels. Altogether, those factors may contribute to the development of abdominal aortic aneurysms.
Figure 7. Figure 7. Features and physiological role of periaortic adipose tissue. Representative histological slices and pictures of both thoracic (tPAAT) and abdominal periaortic adipose tissue (aPAAT) and description of both perivascular adipose tissue (PVAT) features and their physiological role. PAT, periaortic adipose tissue; UCP‐1, uncoupling protein 1; Cidea, cell death activator CIDE‐A; RAS, renin‐angiotensin system; TNF‐α, tumor necrosis factor alpha; MCP‐1, monocyte chemoattractant protein‐1; IL‐6, interleukin‐6; IL‐6R, interleukin‐6 receptor; IL‐18, interleukin‐18; FoxP3, forkhead box P3.
Figure 8. Figure 8. Features and physiological role of mesenteric perivascular adipose tissue. (A) Representative picture of small mesenteric arteries surrounded by mesenteric perivascular adipose tissue (mPVAT). (B) Hystologic slice of a mesenteric artery surrounded by mPVAT. Description of both mesenteric perivascular adipose tissue (mPVAT) features and their physiological role. FAS, fatty acid synthase; HSL, hormone‐sensitive lipase; LPL, lipoprotein lipase; UCP‐1, uncoupling protein 1; NO, nitric oxide; RAS, renin angiotensin system; Ang II, angiotensin II; NA, noradrenaline.
Figure 9. Figure 9. Features and physiological role of periconary adipose tissue. Description of both pericoronary adipose tissue (PCAT) features and their physiological role.
Figure 10. Figure 10. Features and physiological role of saphenous vein perivascular adipose tissue. Representative image of the saphenous vein (SV) and its surrounding perivascular adipose tissue (PVAT) (svPVAT). Description of both svPVAT features and their physiological role. PGE2, prostaglandin E2; PGI2, prostacyclin; CABG, coronary artery bypass grafting.
Figure 11. Figure 11. Pathophysiological consequences of obese perivascular adipose tissue on the vascular wall. Schematic diagram summarizing the pathophysiological consequences of obese perivascular adipose tissue (PVAT) on the vascular wall. In obesity, the increase in perivascular adipocytes size leads to development of dysfunctional adipose tissue because of an altered adipokine profile and an increased secretion of pro‐inflammatory cytokines, both associated with inflammation and hypoxia. Consequently, there is a loss of the PVAT‐derived anticontractile effect. All these changes might contribute to enhance cardiovascular risk factors like insulin resistance, vascular calcification, neointima formation, and arterial stiffness. The direct causal effect of PVAT needs to be further investigated.
Figure 12. Figure 12. Dysfunctional perivascular adipose tissue in obesity. Dysfunctional perivascular adipose tissue (PVAT) results from an imbalance between perivascular relaxing factors (PVRFs) and perivascular contracting factor (PVCFs) in favor of PVCFs. Adiponectin reduction leads to a diminished nitric oxide (NO) release through a reduced phosphorylation of adenosine monophosphate‐activated protein kinase AMP‐protein kinase B‐endothelial nitric oxide synthase phosphorylation (AMPK‐pAkt‐peNOS) and an increase of thromboxane A2 (TXA2) and caveolin‐1 (Cav‐1). Obesity enhances nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity in PVAT through the stimulation of the mitochondrial electron transport chain (mETC), superoxide anion (O− 2), and hydrogen peroxide (H2O2). O− 2 is transformed into H2O2 by the superoxide dismutase (SOD). High levels of O− 2 reduce NO availability and increase oxidative stress. In addition, obesity‐induced adipocytes hypertrophy account for hypoxia and inflammation of PVAT. This is the result of a downregulation of rictor expression that induces an upregulation of mammalian target of rapamycin (mTORC2) and a decreased AMPK activation. mTORC2 induces an increase of proinflammatory markers [tumor necrosis factor‐alpha (TNF‐α), interleukin‐6 (IL‐6), and monocyte chemoattractant protein (MCP‐1)] and inducible nitric oxide synthase (iNOS) activity.
Figure 13. Figure 13. Bidirectional cross talk between the vascular wall and perivascular adipose tissue. Perivascular adipose tissue (PVAT) exerts a paracrine outside‐inside influence on the vascular wall. PVAT‐derived adipokines and cytokines diffuse through the adventitia and the media or through the vasa vasorum to the endothelium and lumen. Under pathological situations, PVAT dysfunction exerts a deleterious influence on the vascular wall. Indeed, dysfunctional PVAT have exhibited an increase of macrophage recruitment, oxidative stress, and inflammation together with a reduction of adiponectin secretion and release, thus leading to a loss of PVAT beneficial effects and aggravating vascular dysfunction (endothelial dysfunction, vascular remodeling, arterial stiffness, and atherosclerosis). Vascular dysfunction might also modulate PVAT function/dysfunction by the inside‐outside diffusion in small vessels or a retrograde transport through the vasa vasorum in conductance vessels.
Figure 14. Figure 14. Role of adiponectin on the vascular wall and perivascular adipose tissue. Schematic representation of the bidirectional signaling of perivascular adipose tissue (PVAT)‐derived adiponectin. The vascular increase in nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) activity stimulates local production of superoxide anion (O− 2) and oxidation products like the 4‐hidroxynonenal (4‐HNE). The latter enhances PPAR‐γ‐mediated ADIPOQ gene expression thus inducing adiponectin synthesis in PVAT. This adiponectin modulates the vascular redox state by regulating endothelial nitric oxide synthase (eNOS) coupling. However, endovascular injury accounts for a reduction of perivascular adipose tissue (PVAT)‐derived adiponectin and the consequent increase of pro‐inflammatory cytokines such as tumor necrosis factor alpha (TNF‐α), interleukin‐6 (IL‐6), plasminogen activator inhibitor‐1 (PAI‐1), and monocyte chemoattractant protein (MCP‐1).


Figure 1. Diagram of histological and ultrastructural cell composition of perivascular adipose tissue. Perivascular adipose tissue (PVAT) differs from other adipose depots in cell composition. PVAT adipocytes (in yellow) constitute the main cellular component of PVAT. In addition, PVAT contains other cell types like preadipocytes, fibroblasts, endothelial cells (in red) and immune cells (macrophages in blue and T cells in black). Those cells constitute the stromal vascular fraction of PVAT. PVAT extracellular matrix is formed by collagen and elastic fibers (in green). PVAT is innervated by the sympathetic nervous system and harbors adrenergic nerve endings.


Figure 2. Perivascular adipose tissue release vasoactive factors thus modulating vascular function and structure. Perivascular adipose tissue (PVAT) surrounding the vascular wall of conductance, resistance arteries and microvessels releases vasoactive factors that can produce either vascular relaxation (perivascular relaxing factors, PVRFs) or vascular contraction (perivascular contractile factors, PVCFs). The direction of the effect on vascular tone, arterial growth and remodeling, extracellular matrix turnover or arterial stiffness depends on the balance between PVRFs and PVCFs.


Figure 3. Anticontractile effect of perivascular adipose tissue in mesenteric artery rings. (A) Representative experiment of vascular function determined by wire myography in isolated mesenteric arteries from wild‐type (C57BL/6) mice with (+) and without (‐) perivascular adipose tissue (PVAT) in response to KCl (6 × 10−2 M) and phenylephrine (PE, 10−8‐10−4 M). In presence of PVAT, contractions to PE but not KCl are lower compared with the mesenteric ring deprived of PVAT. The net beneficial anticontractile effect of PVAT on PE‐contraction is represented in yellow. Adapted, with permission, from (349). (B) Representative concentration‐response curve to PE in mesenteric artery rings (+) PVAT/(−) PVAT, isolated from wild‐type (C57BL/6) mice. Contractions are expressed as the percentage of contraction induced by 6 × 10−2 M KCl. The area between the curves, illustrated in yellow, represents the anti‐contractile effect of PVAT and is reflected by a shifting to the right of the concentration‐response curve to PE. The contraction to PE (10−8‐10−4 M) is significantly higher in arteries without PVAT. *, P < 0.05 compared to (+) PVAT. Adapted, with permission, from (349). (C) Representative concentration‐response curve to PE in mesenteric arteries isolated from PI3Kγ and PI3Kδ deficient mice (Pik3cg–/–/Pik3cd–/–). PI3K (isoforms) are implicated in the regulation of arterial contraction via α1‐adrenergic receptors (agonist PE). Regulation of arterial tone by PVAT occurs without the PI3Kγ and PI3Kδ involvement. The area between the curves, illustrated in blue, represents the anti‐contractile effect of PVAT. The contractile response to PE (10−8‐10−4 M) is significantly higher in arteries without PVAT. *, P < 0.05 compared to (+) PVAT. Adapted, with permission, from (348).


Figure 4. Mechanisms of arterial tone reduction induced by perivascular relaxing factors. Perivascular relaxing factors induce arterial vasodilation through diverse endothelium‐dependent and endothelium‐independent mechanisms. Adipocyte‐derived relaxing factor (ADRF) and palmitic acid methyl ester (PAME) induce vasodilation by opening voltage‐dependent potassium (Kv) channels in vascular smooth muscle cells (VSMC). Hydrogen sulfide (H2S) open both voltage gated Kv7 (KCNQ) and ATP‐dependent K+ (KATP) channels in VSMC. Free fatty acids (FFAs), nitric oxide (NO), and hydrogen peroxide (H2O2) open calcium‐activated potassium (BKCa) channels in VSMC. K+ channels opening leads to an increase in intracellular K+ concentrations thus accounting for VSMCs’ hyperpolarization followed by arterial relaxation. Adiponectin and leptin induce a direct vasodilation through both K+ channel opening in VSMC and NO secretion, due to protein kinase B (Akt) phosphorylation followed by endothelial nitric oxide synthase (eNOS) phosphorylation at Ser1177. Leptin also increases endothelium‐derived hyperpolarization factor (EDHF) levels. Omentin activates adenosine monophosphate‐activated protein kinase AMP‐(AMPK) signalling in endothelial cells (EC) and stimulate eNOS phosphorylation at Ser1177 thus increasing NO availability.


Figure 5. Mechanisms of putative PVRFs’ regulation of vascular tone. Effects of exercise on skeletal muscle are mediated by the transcriptional peroxisome proliferator‐activated receptor gamma coactivator 1‐α (PGC1α). PGC1α stimulates an increase in the expression of fibronectin type III domain‐containing protein 5 (FNDC5). The FNDC5 gene encodes a type I membrane protein known as irisin. Perivascular adipose tissue (PVAT)‐derived irisin increases uncoupling protein 1 (UCP‐1) and cell death activator CIDE‐A (Cidea) expression, thus enhancing browning of PVAT. Those effects are accompanied by the upregulation of the heme oxygenase‐1 (HO‐1) followed by a reduction in pro‐inflammatory cytokines (tumor necrosis factor alpha, TNF‐α) and CD3 and oxidative stress (superoxide anion, O2 −) as well as an increase in adiponectin levels. The latter activates endothelial adenosine monophosphate‐activated protein kinase AMP (AMPK) that induces endothelial nitric oxide synthase (eNOS) phosphorylation, thus accounting for nitric oxide (NO) release and vasorelaxation.


Figure 6. Physiological and pathological role of the renin‐angiotensin system in periaortic adipose tissue. All components of the renin‐angiotensin system (RAS) are expressed or synthesized in perivascular adipose tissue (PVAT) of rat aorta. The physiological role of PVAT‐derived RAS peptides seems to be dual: (i) Angiotensin II (Ang II), when bound to AT1 receptors, increases adrenergic activity, thus enhancing noradrenaline (NA) levels and VSMCs’ contractions; (ii) Angiotensin (1,2,3,4,5,6,7) induces relaxation of VSMCs through the endothelial Mas receptor. However, in obesity, AT1 activation by abdominal periaortic adipose tissue (aPAAT)‐derived Ang II increases inflammation in aPAAT, favoring the entry of periadventitial leukocytes into the vascular wall together with an increase in the expression of proinflammatory cytokines (tumor necrosis factor alpha, TNF‐α, interleukin 6, IL‐6) and matrix metalloproteinase‐2 (MMP‐2) as well as an enhancement of aldosterone levels. Altogether, those factors may contribute to the development of abdominal aortic aneurysms.


Figure 7. Features and physiological role of periaortic adipose tissue. Representative histological slices and pictures of both thoracic (tPAAT) and abdominal periaortic adipose tissue (aPAAT) and description of both perivascular adipose tissue (PVAT) features and their physiological role. PAT, periaortic adipose tissue; UCP‐1, uncoupling protein 1; Cidea, cell death activator CIDE‐A; RAS, renin‐angiotensin system; TNF‐α, tumor necrosis factor alpha; MCP‐1, monocyte chemoattractant protein‐1; IL‐6, interleukin‐6; IL‐6R, interleukin‐6 receptor; IL‐18, interleukin‐18; FoxP3, forkhead box P3.


Figure 8. Features and physiological role of mesenteric perivascular adipose tissue. (A) Representative picture of small mesenteric arteries surrounded by mesenteric perivascular adipose tissue (mPVAT). (B) Hystologic slice of a mesenteric artery surrounded by mPVAT. Description of both mesenteric perivascular adipose tissue (mPVAT) features and their physiological role. FAS, fatty acid synthase; HSL, hormone‐sensitive lipase; LPL, lipoprotein lipase; UCP‐1, uncoupling protein 1; NO, nitric oxide; RAS, renin angiotensin system; Ang II, angiotensin II; NA, noradrenaline.


Figure 9. Features and physiological role of periconary adipose tissue. Description of both pericoronary adipose tissue (PCAT) features and their physiological role.


Figure 10. Features and physiological role of saphenous vein perivascular adipose tissue. Representative image of the saphenous vein (SV) and its surrounding perivascular adipose tissue (PVAT) (svPVAT). Description of both svPVAT features and their physiological role. PGE2, prostaglandin E2; PGI2, prostacyclin; CABG, coronary artery bypass grafting.


Figure 11. Pathophysiological consequences of obese perivascular adipose tissue on the vascular wall. Schematic diagram summarizing the pathophysiological consequences of obese perivascular adipose tissue (PVAT) on the vascular wall. In obesity, the increase in perivascular adipocytes size leads to development of dysfunctional adipose tissue because of an altered adipokine profile and an increased secretion of pro‐inflammatory cytokines, both associated with inflammation and hypoxia. Consequently, there is a loss of the PVAT‐derived anticontractile effect. All these changes might contribute to enhance cardiovascular risk factors like insulin resistance, vascular calcification, neointima formation, and arterial stiffness. The direct causal effect of PVAT needs to be further investigated.


Figure 12. Dysfunctional perivascular adipose tissue in obesity. Dysfunctional perivascular adipose tissue (PVAT) results from an imbalance between perivascular relaxing factors (PVRFs) and perivascular contracting factor (PVCFs) in favor of PVCFs. Adiponectin reduction leads to a diminished nitric oxide (NO) release through a reduced phosphorylation of adenosine monophosphate‐activated protein kinase AMP‐protein kinase B‐endothelial nitric oxide synthase phosphorylation (AMPK‐pAkt‐peNOS) and an increase of thromboxane A2 (TXA2) and caveolin‐1 (Cav‐1). Obesity enhances nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity in PVAT through the stimulation of the mitochondrial electron transport chain (mETC), superoxide anion (O− 2), and hydrogen peroxide (H2O2). O− 2 is transformed into H2O2 by the superoxide dismutase (SOD). High levels of O− 2 reduce NO availability and increase oxidative stress. In addition, obesity‐induced adipocytes hypertrophy account for hypoxia and inflammation of PVAT. This is the result of a downregulation of rictor expression that induces an upregulation of mammalian target of rapamycin (mTORC2) and a decreased AMPK activation. mTORC2 induces an increase of proinflammatory markers [tumor necrosis factor‐alpha (TNF‐α), interleukin‐6 (IL‐6), and monocyte chemoattractant protein (MCP‐1)] and inducible nitric oxide synthase (iNOS) activity.


Figure 13. Bidirectional cross talk between the vascular wall and perivascular adipose tissue. Perivascular adipose tissue (PVAT) exerts a paracrine outside‐inside influence on the vascular wall. PVAT‐derived adipokines and cytokines diffuse through the adventitia and the media or through the vasa vasorum to the endothelium and lumen. Under pathological situations, PVAT dysfunction exerts a deleterious influence on the vascular wall. Indeed, dysfunctional PVAT have exhibited an increase of macrophage recruitment, oxidative stress, and inflammation together with a reduction of adiponectin secretion and release, thus leading to a loss of PVAT beneficial effects and aggravating vascular dysfunction (endothelial dysfunction, vascular remodeling, arterial stiffness, and atherosclerosis). Vascular dysfunction might also modulate PVAT function/dysfunction by the inside‐outside diffusion in small vessels or a retrograde transport through the vasa vasorum in conductance vessels.


Figure 14. Role of adiponectin on the vascular wall and perivascular adipose tissue. Schematic representation of the bidirectional signaling of perivascular adipose tissue (PVAT)‐derived adiponectin. The vascular increase in nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) activity stimulates local production of superoxide anion (O− 2) and oxidation products like the 4‐hidroxynonenal (4‐HNE). The latter enhances PPAR‐γ‐mediated ADIPOQ gene expression thus inducing adiponectin synthesis in PVAT. This adiponectin modulates the vascular redox state by regulating endothelial nitric oxide synthase (eNOS) coupling. However, endovascular injury accounts for a reduction of perivascular adipose tissue (PVAT)‐derived adiponectin and the consequent increase of pro‐inflammatory cytokines such as tumor necrosis factor alpha (TNF‐α), interleukin‐6 (IL‐6), plasminogen activator inhibitor‐1 (PAI‐1), and monocyte chemoattractant protein (MCP‐1).
References
 1. Aalbaek F , Bonde L , Kim S , Boedtkjer E . Perivascular tissue inhibits rho‐kinase‐dependent smooth muscle Ca(2+) sensitivity and endothelium‐dependent H2 S signalling in rat coronary arteries. J Physiol 593: 4747‐4764, 2015.
 2. Aghamohammadzadeh R , Greenstein AS , Yadav R , Jeziorska M , Hama S , Soltani F , Pemberton PW , Ammori B , Malik RA , Soran H , Heagerty AM . Effects of bariatric surgery on human small artery function: evidence for reduction in perivascular adipocyte inflammation, and the restoration of normal anticontractile activity despite persistent obesity. J Am Coll Cardiol 62: 128‐135, 2013.
 3. Aghamohammadzadeh R , Unwin RD , Greenstein AS , Heagerty AM . Effects of obesity on perivascular adipose tissue vasorelaxant function: Nitric oxide, inflammation and elevated systemic blood pressure. J Vasc Res 52: 299‐305, 2015.
 4. Ahmed SR , Johansson BL , Karlsson MG , Souza DS , Dashwood MR , Loesch A . Human saphenous vein and coronary bypass surgery: Ultrastructural aspects of conventional and “no‐touch” vein graft preparations. Histol Histopathol 19: 421‐433, 2004.
 5. Al Chekakie MO , Welles CC , Metoyer R , Ibrahim A , Shapira AR , Cytron J , Santucci P , Wilber DJ , Akar JG . Pericardial fat is independently associated with human atrial fibrillation. J Am Coll Cardiol 56: 784‐788, 2010.
 6. Alexander MR , Moehle CW , Johnson JL , Yang Z , Lee JK , Jackson CL , Owens GK . Genetic inactivation of IL‐1 signaling enhances atherosclerotic plaque instability and reduces outward vessel remodeling in advanced atherosclerosis in mice. J Clin Invest 122: 70‐79, 2012.
 7. Almabrouk TA , Ugusman AB , Katwan OJ , Salt IP , Kennedy S . Deletion of AMPKalpha1 attenuates the anticontractile effect of perivascular adipose tissue (PVAT) and reduces adiponectin release. Br J Pharmacol, 2016.
 8. Andreeva ER , Lobanova MV , Udartseva OO , Buravkova LB . Response of adipose tissue‐derived stromal cells in tissue‐related O2 microenvironment to short‐term hypoxic stress. Cells Tissues Organs 200: 307‐315, 2015.
 9. Antonopoulos AS , Margaritis M , Coutinho P , Shirodaria C , Psarros C , Herdman L , Sanna F , De Silva R , Petrou M , Sayeed R , Krasopoulos G , Lee R , Digby J , Reilly S , Bakogiannis C , Tousoulis D , Kessler B , Casadei B , Channon KM , Antoniades C . Adiponectin as a link between type 2 diabetes and vascular NADPH oxidase activity in the human arterial wall: The regulatory role of perivascular adipose tissue. Diabetes 64: 2207‐2219, 2015.
 10. Ardanaz N , Pagano PJ. Hydrogen peroxide as a paracrine vascular mediator: Regulation and signaling leading to dysfunction. Exp Biol Med (Maywood) 231: 237‐251, 2006.
 11. Bailey‐Downs LC , Tucsek Z , Toth P , Sosnowska D , Gautam T , Sonntag WE , Csiszar A , Ungvari Z . Aging exacerbates obesity‐induced oxidative stress and inflammation in perivascular adipose tissue in mice: A paracrine mechanism contributing to vascular redox dysregulation and inflammation. J Gerontol A Biol Sci Med Sci 68: 780‐792, 2013.
 12. Barandier C , Montani JP , Yang Z . Mature adipocytes and perivascular adipose tissue stimulate vascular smooth muscle cell proliferation: Effects of aging and obesity. Am J Physiol Heart Circ Physiol 289: H1807‐H1813, 2005.
 13. Batten P , Yacoub MH , Rose ML . Effect of human cytokines (IFN‐gamma, TNF‐alpha, IL‐1 beta, IL‐4) on porcine endothelial cells: Induction of MHC and adhesion molecules and functional significance of these changes. Immunology 87: 127‐133, 1996.
 14. Beasley D , Cohen RA , Levinsky NG . Interleukin 1 inhibits contraction of vascular smooth muscle. J Clin Invest 83: 331‐335, 1989.
 15. Beer‐Hammer S , Zebedin E , von Holleben M , Alferink J , Reis B , Dresing P , Degrandi D , Scheu S , Hirsch E , Sexl V , Pfeffer K , Nurnberg B , Piekorz RP . The catalytic PI3K isoforms p110gamma and p110delta contribute to B cell development and maintenance, transformation, and proliferation. J Leukoc Biol 87: 1083‐1095, 2010.
 16. Beltowski J , Guranowski A , Jamroz‐Wisniewska A , Wolski A , Halas K . Hydrogen‐sulfide‐mediated vasodilatory effect of nucleoside 5′‐monophosphorothioates in perivascular adipose tissue. Can J Physiol Pharmacol 93: 585‐595, 2015.
 17. Berg AH , Combs TP , Scherer PE . ACRP30/adiponectin: An adipokine regulating glucose and lipid metabolism. Trends Endocrinol Metab 13: 84‐89, 2002.
 18. Berti L , Hartwig S , Irmler M , Radle B , Siegel‐Axel D , Beckers J , Lehr S , Al‐Hasani H , Haring HU , Hrabe de Angelis M , Staiger H . Impact of fibroblast growth factor 21 on the secretome of human perivascular preadipocytes and adipocytes: A targeted proteomics approach. Arch Physiol Biochem 122: 281‐288, 2016.
 19. Berwick ZC , Dick GM , Tune JD . Heart of the matter: Coronary dysfunction in metabolic syndrome. J Mol Cell Cardiol 52: 848‐856, 2012.
 20. Bhattacharya I , Dragert K , Albert V , Contassot E , Damjanovic M , Hagiwara A , Zimmerli L , Humar R , Hall MN , Battegay EJ , Haas E . Rictor in perivascular adipose tissue controls vascular function by regulating inflammatory molecule expression. Arterioscler Thromb Vasc Biol 33: 2105‐2111, 2013.
 21. Boesen EI , Pollock DM. Effect of chronic IL‐6 infusion on acute pressor responses to vasoconstrictors in mice. Am J Physiol Heart Circ Physiol 293: H1745‐H1749, 2007.
 22. Boland LM , Drzewiecki MM. Polyunsaturated fatty acid modulation of voltage‐gated ion channels. Cell Biochem Biophys 52: 59‐84, 2008.
 23. Bonadonna RC , Saccomani MP , Del Prato S , Bonora E , DeFronzo RA , Cobelli C . Role of tissue‐specific blood flow and tissue recruitment in insulin‐mediated glucose uptake of human skeletal muscle. Circulation 98: 234‐241, 1998.
 24. Bostrom P , Wu J , Jedrychowski MP , Korde A , Ye L , Lo JC , Rasbach KA , Bostrom EA , Choi JH , Long JZ , Kajimura S , Zingaretti MC , Vind BF , Tu H , Cinti S , Hojlund K , Gygi SP , Spiegelman BM . A PGC1‐alpha‐dependent myokine that drives brown‐fat‐like development of white fat and thermogenesis. Nature 481: 463‐468, 2012.
 25. Boucher J , Masri B , Daviaud D , Gesta S , Guigne C , Mazzucotelli A , Castan‐Laurell I , Tack I , Knibiehler B , Carpene C , Audigier Y , Saulnier‐Blache JS , Valet P . Apelin, a newly identified adipokine up‐regulated by insulin and obesity. Endocrinology 146: 1764‐1771, 2005.
 26. Bourlier V , Zakaroff‐Girard A , Miranville A , De Barros S , Maumus M , Sengenes C , Galitzky J , Lafontan M , Karpe F , Frayn KN , Bouloumie A . Remodeling phenotype of human subcutaneous adipose tissue macrophages. Circulation 117: 806‐815, 2008.
 27. Boydens C , Maenhaut N , Pauwels B , Decaluwe K , Van de Voorde J . Adipose tissue as regulator of vascular tone. Curr Hypertens Rep 14: 270‐278, 2012.
 28. Brian JE, Jr. , Faraci FM. Tumor necrosis factor‐alpha‐induced dilatation of cerebral arterioles. Stroke 29: 509‐515, 1998.
 29. Britton KA , Wang N , Palmisano J , Corsini E , Schlett CL , Hoffmann U , Larson MG , Vasan RS , Vita JA , Mitchell GF , Benjamin EJ , Hamburg NM , Fox CS . Thoracic periaortic and visceral adipose tissue and their cross‐sectional associations with measures of vascular function. Obesity 21: 1496‐1503, 2013.
 30. Brown NK , Zhou Z , Zhang J , Zeng R , Wu J , Eitzman DT , Chen YE , Chang L . Perivascular adipose tissue in vascular function and disease: A review of current research and animal models. Arterioscler Thromb Vasc Biol 34: 1621‐1630, 2014.
 31. Bulloch JM , Daly CJ. Autonomic nerves and perivascular fat: interactive mechanisms. Pharmacol Ther 143: 61‐73, 2014.
 32. Bussey CE , Withers SB , Aldous RG , Edwards G , Heagerty AM . Obesity‐related perivascular adipose tissue damage is reversed by sustained weight loss in the rat. Arterioscler Thromb Vasc Biol 36: 1377‐1385, 2016.
 33. Bussey CT , Kolka CM , Rattigan S , Richards SM . Adiponectin opposes endothelin‐1‐mediated vasoconstriction in the perfused rat hindlimb. J Physiol Heart Circ Physiol 301: H79‐H86, 2011.
 34. Cai H. Hydrogen peroxide regulation of endothelial function: Origins, mechanisms, and consequences. Cardiovasc Res 68: 26‐36, 2005.
 35. Calabro P , Samudio I , Willerson JT , Yeh ET . Resistin promotes smooth muscle cell proliferation through activation of extracellular signal‐regulated kinase 1/2 and phosphatidylinositol 3‐kinase pathways. Circulation 110: 3335‐3340, 2004.
 36. Carlyle M , Jones OB , Kuo JJ , Hall JE . Chronic cardiovascular and renal actions of leptin: role of adrenergic activity. Hypertension 39: 496‐501, 2002.
 37. Caspar‐Bauguil S , Cousin B , Galinier A , Segafredo C , Nibbelink M , Andre M , Casteilla L , Penicaud L . Adipose tissues as an ancestral immune organ: site‐specific change in obesity. FEBS Lett 579: 3487‐3492, 2005.
 38. Cassis LA , Police SB , Yiannikouris F , Thatcher SE . Local adipose tissue renin‐angiotensin system. Curr Hypertens Rep 10: 93‐98, 2008.
 39. Cassis LA , Rateri DL , Lu H , Daugherty A . Bone marrow transplantation reveals that recipient AT1a receptors are required to initiate angiotensin II‐induced atherosclerosis and aneurysms. Arterioscler Thromb Vasc Biol 27: 380‐386, 2007.
 40. Castillo C , Cruzado M , Ariznavarreta C , Gil‐Loyzaga P , Lahera V , Cachofeiro V , Tresguerres JA . Effect of recombinant human growth hormone administration on body composition and vascular function and structure in old male Wistar rats. Biogerontology 6: 303‐312, 2005.
 41. Cinti S. Adipose tissues and obesity. Ital J Anat Embryol 104: 37‐51, 1999.
 42. Claria J , Nguyen BT , Madenci AL , Ozaki CK , Serhan CN . Diversity of lipid mediators in human adipose tissue depots. Am J Physiol Cell Physiol 304: C1141‐C1149, 2013.
 43. Cleveland‐Donovan K , Maile LA , Tsiaras WG , Tchkonia T , Kirkland JL , Boney CM . IGF‐I activation of the AKT pathway is impaired in visceral but not subcutaneous preadipocytes from obese subjects. Endocrinology 151: 3752‐3763, 2010.
 44. Corvino A , Severino B , Fiorino F , Frecentese F , Magli E , Perissutti E , Santagada V , Bucci M , Cirino G , Kelly G , Servillo L , Popowicz G , Pastore A , Caliendo G . Fragment‐based de novo design of a cystathionine gamma‐lyase selective inhibitor blocking hydrogen sulfide production. Sci Rep 6: 34398, 2016.
 45. Costa IA , Hein TW , Secombes CJ , Gamperl AK . Recombinant interleukin‐1beta dilates steelhead trout coronary microvessels: effect of temperature and role of the endothelium, nitric oxide and prostaglandins. J Exp Biol 218: 2269‐2278, 2015.
 46. Costa RM , Filgueira FP , Tostes RC , Carvalho MH , Akamine EH , Lobato NS . H2O2 generated from mitochondrial electron transport chain in thoracic perivascular adipose tissue is crucial for modulation of vascular smooth muscle contraction. Vascul Pharmacol 84: 28‐37, 2016.
 47. Chae CU , Lee RT , Rifai N , Ridker PM . Blood pressure and inflammation in apparently healthy men. Hypertension 38: 399‐403, 2001.
 48. Chang L , Villacorta L , Li R , Hamblin M , Xu W , Dou C , Zhang J , Wu J , Zeng R , Chen YE . Loss of perivascular adipose tissue on peroxisome proliferator‐activated receptor‐gamma deletion in smooth muscle cells impairs intravascular thermoregulation and enhances atherosclerosis. Circulation 126: 1067‐1078, 2012.
 49. Chatterjee TK , Aronow BJ , Tong WS , Manka D , Tang Y , Bogdanov VY , Unruh D , Blomkalns AL , Piegore MG, Jr. , Weintraub DS , Rudich SM , Kuhel DG , Hui DY , Weintraub NL . Human coronary artery perivascular adipocytes overexpress genes responsible for regulating vascular morphology, inflammation, and hemostasis. Physiol Genomics 45: 697‐709, 2013.
 50. Chatterjee TK , Stoll LL , Denning GM , Harrelson A , Blomkalns AL , Idelman G , Rothenberg FG , Neltner B , Romig‐Martin SA , Dickson EW , Rudich S , Weintraub NL . Proinflammatory phenotype of perivascular adipocytes: Influence of high‐fat feeding. Circ Res 104: 541‐549, 2009.
 51. Chen C , Jiang J , Lu JM , Chai H , Wang X , Lin PH , Yao Q . Resistin decreases expression of endothelial nitric oxide synthase through oxidative stress in human coronary artery endothelial cells. J Physiol Heart Circ Physiol 299: H193‐H201, 2010.
 52. Chen D , Lee J , Gu X , Wei L , Yu SP . Intranasal delivery of apelin‐13 is neuroprotective and promotes angiogenesis after ischemic stroke in mice. ASN Neuro 7: pii: 1759091415605114, 2015.
 53. Chen H , Montagnani M , Funahashi T , Shimomura I , Quon MJ . Adiponectin stimulates production of nitric oxide in vascular endothelial cells. J Biol Chem 278: 45021‐45026, 2003.
 54. Chen J , Gu Z , Wu M , Yang Y , Zhang J , Ou J , Zuo Z , Wang J , Chen Y . C‐reactive protein can upregulate VEGF expression to promote ADSC‐induced angiogenesis by activating HIF‐1alpha via CD64/PI3k/Akt and MAPK/ERK signaling pathways. Stem Cell Res Ther 7: 114, 2016.
 55. Chen JY , Tsai PJ , Tai HC , Tsai RL , Chang YT , Wang MC , Chiou YW , Yeh ML , Tang MJ , Lam CF , Shiesh SC , Li YH , Tsai WC , Chou CH , Lin LJ , Wu HL , Tsai YS . Increased aortic stiffness and attenuated lysyl oxidase activity in obesity. Arterioscler Thromb Vasc Biol 33: 839‐846, 2013.
 56. Chen Y , Wang X , Mai J , Zhao X , Liang Y , Gu M , Chen Z , Nie R , Wang J . C‐reactive protein promotes vascular endothelial dysfunction partly via activating adipose tissue inflammation in hyperlipidemic rabbits. Int J Cardiol 168: 2397‐2403, 2013.
 57. Cheng KK , Lam KS , Wang Y , Huang Y , Carling D , Wu D , Wong C , Xu A . Adiponectin‐induced endothelial nitric oxide synthase activation and nitric oxide production are mediated by APPL1 in endothelial cells. Diabetes 56: 1387‐1394, 2007.
 58. Cheranov SY , Jaggar JH. TNF‐alpha dilates cerebral arteries via NAD(P)H oxidase‐dependent Ca2+ spark activation. Am J Physiol Cell Physiol 290: C964‐C971, 2006.
 59. Chin LC , Achike FI , Mustafa MR . Hydrogen peroxide modulates angiotensin II‐induced contraction of mesenteric arteries from streptozotocin‐induced diabetic rats. Vascul Pharmacol 46: 223‐228, 2007.
 60. Cho YL , Hur SM , Kim JY , Kim JH , Lee DK , Choe J , Won MH , Ha KS , Jeoung D , Han S , Ryoo S , Lee H , Min JK , Kwon YG , Kim DH , Kim YM . Specific activation of insulin‐like growth factor‐1 receptor by ginsenoside Rg5 promotes angiogenesis and vasorelaxation. J Biol Chem 290: 467‐477, 2015.
 61. Chudek J , Wiecek A. Adipose tissue, inflammation and endothelial dysfunction. Pharmacol Rep 58(Suppl): 81‐88, 2006.
 62. Chughtai HL , Morgan TM , Rocco M , Stacey B , Brinkley TE , Ding J , Nicklas B , Hamilton C , Hundley WG . Renal sinus fat and poor blood pressure control in middle‐aged and elderly individuals at risk for cardiovascular events. Hypertension 56: 901‐906, 2010.
 63. Chun HJ , Ali ZA , Kojima Y , Kundu RK , Sheikh AY , Agrawal R , Zheng L , Leeper NJ , Pearl NE , Patterson AJ , Anderson JP , Tsao PS , Lenardo MJ , Ashley EA , Quertermous T . Apelin signaling antagonizes Ang II effects in mouse models of atherosclerosis. J Clin Invest 118: 3343‐3354, 2008.
 64. Dabek J , Kulach A , Gasior Z . Nuclear factor kappa‐light‐chain‐enhancer of activated B cells (NF‐kappaB): A new potential therapeutic target in atherosclerosis? Pharmacol Rep 62: 778‐783, 2010.
 65. Dahl TB , Yndestad A , Skjelland M , Oie E , Dahl A , Michelsen A , Damas JK , Tunheim SH , Ueland T , Smith C , Bendz B , Tonstad S , Gullestad L , Froland SS , Krohg‐Sorensen K , Russell D , Aukrust P , Halvorsen B . Increased expression of visfatin in macrophages of human unstable carotid and coronary atherosclerosis: Possible role in inflammation and plaque destabilization. Circulation 115: 972‐980, 2007.
 66. Dashwood MR , Angelini GD , Wan S , Yim A , Mehta D , Izzat MB , Jeremy JY . Does external stenting reduce porcine vein‐graft occlusion via an action on vascular nerves? J Card Surg 17: 556‐560, 2002.
 67. Dashwood MR , Dooley A , Shi‐Wen X , Abraham DJ , Dreifaldt M , Souza DS . Perivascular fat‐derived leptin: a potential role in improved vein graft performance in coronary artery bypass surgery. Interact Cardiovasc Thorac Surg 12: 170‐173, 2011.
 68. Dashwood MR , Dooley A , Shi‐Wen X , Abraham DJ , Souza DS . Does periadventitial fat‐derived nitric oxide play a role in improved saphenous vein graft patency in patients undergoing coronary artery bypass surgery? J Vasc Res 44: 175‐181, 2007.
 69. Dashwood MR , Gibbins R , Mehta D , Bashar Izzat M , Angelini GD , Jeremy JY . Neural reorganisation in porcine vein grafts: A potential role for endothelin‐1. Atherosclerosis 150: 43‐53, 2000.
 70. Dashwood MR , Loesch A. The saphenous vein as a bypass conduit: The potential role of vascular nerves in graft performance. Curr Vasc Pharmacol 7: 47‐57, 2009.
 71. Dashwood MR , Souza DS , Fernandez‐Alfonso MS . Re: Perivascular tissue of internal thoracic artery releases potent nitric oxide and prostacyclin‐independent anticontractile factor. Eur J Cardiothorac Surg 33: 1161‐1162; author reply 1162‐1163, 2008.
 72. Dick GM , Katz PS , Farias M, 3rd , Morris M , James J , Knudson JD , Tune JD . Resistin impairs endothelium‐dependent dilation to bradykinin, but not acetylcholine, in the coronary circulation. J Physiol Heart Circ Physiol 291: H2997‐H3002, 2006.
 73. Diculescu I , Stoica M. Fluorescence histochemical investigation on the adrenergic innervation of the white adipose tissue in the rat. J Neurovisc Relat 32: 25‐36, 1970.
 74. Diez JJ , Iglesias P. The role of the novel adipocyte‐derived hormone adiponectin in human disease. Eur J Endocrinol 148: 293‐300, 2003.
 75. Ding J , Kritchevsky SB , Harris TB , Burke GL , Detrano RC , Szklo M , Jeffrey Carr J , Multi‐Ethnic Study of A. The association of pericardial fat with calcified coronary plaque. Obesity 16: 1914‐1919, 2008.
 76. Dorrance AM. Interleukin 1‐beta (IL‐1beta) enhances contractile responses in endothelium‐denuded aorta from hypertensive, but not normotensive, rats. Vascul Pharmacol 47: 160‐165, 2007.
 77. Drake AJ , Reynolds RM. Impact of maternal obesity on offspring obesity and cardiometabolic disease risk. Reproduction 140: 387‐398, 2010.
 78. Dreifaldt M , Mannion JD , Bodin L , Olsson H , Zagozdzon L , Souza D . The no‐touch saphenous vein as the preferred second conduit for coronary artery bypass grafting. Ann Thorac Surg 96: 105‐111, 2013.
 79. Dreifaldt M , Souza D , Bodin L , Shi‐Wen X , Dooley A , Muddle J , Loesch A , Dashwood MR . The vasa vasorum and associated endothelial nitric oxide synthase is more important for saphenous vein than arterial bypass grafts. Angiology 64: 293‐299, 2013.
 80. Du B , Ouyang A , Eng JS , Fleenor BS . Aortic perivascular adipose‐derived interleukin‐6 contributes to arterial stiffness in low‐density lipoprotein receptor deficient mice. J Physiol Heart Circ Physiol 308: H1382‐H1390, 2015.
 81. Duan XY , Xie PL , Ma YL , Tang SY . Omentin inhibits osteoblastic differentiation of calcifying vascular smooth muscle cells through the PI3K/Akt pathway. Amino Acids 41: 1223‐1231, 2011.
 82. Dwyer TM , Carroll JF , Mizelle HL , Cockrell K . Renal size and composition in hypertensive, obese rabbits. Int J Obes Relat Metab Disord 22: 935‐938, 1998.
 83. Dwyer TM , Mizelle HL , Cockrell K , Buhner P . Renal sinus lipomatosis and body composition in hypertensive, obese rabbits. Int J Obes Relat Metab Disord 19: 869‐874, 1995.
 84. Egawa G , Miyachi Y , Kabashima K . Identification of perivascular adipose tissue in the mouse skin using two‐photon microscopy. J Dermatol Sci 70: 139‐140, 2013.
 85. El Khoudary SR , Shields KJ , Janssen I , Hanley C , Budoff MJ , Barinas‐Mitchell E , Everson‐Rose SA , Powell LH , Matthews KA . Cardiovascular fat, menopause, and sex hormones in women: The SWAN Cardiovascular Fat Ancillary Study. J Clin Endocrinol Metab 100: 3304‐3312, 2015.
 86. Emilova R , Dimitrova DZ , Mladenov M , Hadzi‐Petrushev N , Daneva T , Padeshki P , Schubert R , Chichova M , Lubomirov L , Simeonovska‐Nikolova D , Gagov H . Diabetes converts arterial regulation by perivascular adipose tissue from relaxation into H(2)O(2)‐mediated contraction. Physiol Res 65: 799‐807, 2016.
 87. Engeli S , Feldpausch M , Gorzelniak K , Hartwig F , Heintze U , Janke J , Mohlig M , Pfeiffer AF , Luft FC , Sharma AM . Association between adiponectin and mediators of inflammation in obese women. Diabetes 52: 942‐947, 2003.
 88. Engeli S , Gorzelniak K , Kreutz R , Runkel N , Distler A , Sharma AM . Co‐expression of renin‐angiotensin system genes in human adipose tissue. J Hypertens 17: 555‐560, 1999.
 89. Erdei N , Bagi Z , Edes I , Kaley G , Koller A . H2O2 increases production of constrictor prostaglandins in smooth muscle leading to enhanced arteriolar tone in Type 2 diabetic mice. J Physiol Heart Circ Physiol 292: H649‐H656, 2007.
 90. Eringa EC , Bakker W , Smulders YM , Serne EH , Yudkin JS , Stehouwer CD . Regulation of vascular function and insulin sensitivity by adipose tissue: focus on perivascular adipose tissue. Microcirculation 14: 389‐402, 2007.
 91. Eringa EC , Stehouwer CD , Merlijn T , Westerhof N , Sipkema P . Physiological concentrations of insulin induce endothelin‐mediated vasoconstriction during inhibition of NOS or PI3‐kinase in skeletal muscle arterioles. Cardiovasc Res 56: 464‐471, 2002.
 92. Fagerberg L , Hallstrom BM , Oksvold P , Kampf C , Djureinovic D , Odeberg J , Habuka M , Tahmasebpoor S , Danielsson A , Edlund K , Asplund A , Sjostedt E , Lundberg E , Szigyarto CA , Skogs M , Takanen JO , Berling H , Tegel H , Mulder J , Nilsson P , Schwenk JM , Lindskog C , Danielsson F , Mardinoglu A , Sivertsson A , von Feilitzen K , Forsberg M , Zwahlen M , Olsson I , Navani S , Huss M , Nielsen J , Ponten F , Uhlen M . Analysis of the human tissue‐specific expression by genome‐wide integration of transcriptomics and antibody‐based proteomics. Mol Cell Proteomics 13: 397‐406, 2014.
 93. Fang L , Zhao J , Chen Y , Ma T , Xu G , Tang C , Liu X , Geng B . Hydrogen sulfide derived from periadventitial adipose tissue is a vasodilator. J Hypertens 27: 2174‐2185, 2009.
 94. Fesus G , Dubrovska G , Gorzelniak K , Kluge R , Huang Y , Luft FC , Gollasch M . Adiponectin is a novel humoral vasodilator. Cardiovasc Res 75: 719‐727, 2007.
 95. Fitzgibbons TP , Czech MP. Epicardial and perivascular adipose tissues and their influence on cardiovascular disease: Basic mechanisms and clinical associations. J Am Heart Assoc 3: e000582, 2014.
 96. Fitzgibbons TP , Kogan S , Aouadi M , Hendricks GM , Straubhaar J , Czech MP . Similarity of mouse perivascular and brown adipose tissues and their resistance to diet‐induced inflammation. J Physiol Heart Circ Physiol 301: H1425‐H1437, 2011.
 97. Fleenor BS , Eng JS , Sindler AL , Pham BT , Kloor JD , Seals DR . Superoxide signaling in perivascular adipose tissue promotes age‐related artery stiffness. Aging Cell 13: 576‐578, 2014.
 98. Foster MC , Hwang SJ , Porter SA , Massaro JM , Hoffmann U , Fox CS . Fatty kidney, hypertension, and chronic kidney disease: The Framingham Heart Study. Hypertension 58: 784‐790, 2011.
 99. Fox CS , Massaro JM , Schlett CL , Lehman SJ , Meigs JB , O'Donnell CJ , Hoffmann U , Murabito JM . Periaortic fat deposition is associated with peripheral arterial disease: The Framingham heart study. Circ Cardiovasc Imaging 3: 515‐519, 2010.
 100. Frayn KN , Tan GD , Karpe F . Adipose tissue: A key target for diabetes pathophysiology and treatment? Horm Metab Res 39: 739‐742, 2007.
 101. Fruhbeck G. Pivotal role of nitric oxide in the control of blood pressure after leptin administration. Diabetes 48: 903‐908, 1999.
 102. Fusaru AM , Pisoschi CG , Bold A , Taisescu C , Stanescu R , Hincu M , Craitoiu S , Banita IM . Hypoxia induced VEGF synthesis in visceral adipose depots of obese diabetic patients. Rom J Morphol Embryol 53: 903‐909, 2012.
 103. Gaborit B , Venteclef N , Ancel P , Pelloux V , Gariboldi V , Leprince P , Amour J , Hatem SN , Jouve E , Dutour A , Clement K . Human epicardial adipose tissue has a specific transcriptomic signature depending on its anatomical peri‐atrial, peri‐ventricular, or peri‐coronary location. Cardiovasc Res 108: 62‐73, 2015.
 104. Galvez‐Prieto B , Bolbrinker J , Stucchi P , de Las Heras AI , Merino B , Arribas S , Ruiz‐Gayo M , Huber M , Wehland M , Kreutz R , Fernandez‐Alfonso MS . Comparative expression analysis of the renin‐angiotensin system components between white and brown perivascular adipose tissue. J Endocrinol 197: 55‐64, 2008.
 105. Galvez‐Prieto B , Dubrovska G , Cano MV , Delgado M , Aranguez I , Gonzalez MC , Ruiz‐Gayo M , Gollasch M , Fernandez‐Alfonso MS . A reduction in the amount and anti‐contractile effect of periadventitial mesenteric adipose tissue precedes hypertension development in spontaneously hypertensive rats. Hypertens Res 31: 1415‐1423, 2008.
 106. Galvez‐Prieto B , Somoza B , Gil‐Ortega M , Garcia‐Prieto CF , de Las Heras AI , Gonzalez MC , Arribas S , Aranguez I , Bolbrinker J , Kreutz R , Ruiz‐Gayo M , Fernandez‐Alfonso MS . Anticontractile effect of perivascular adipose tissue and leptin are reduced in hypertension. Front Pharmacol 3: 103, 2012.
 107. Galvez B , de Castro J , Herold D , Dubrovska G , Arribas S , Gonzalez MC , Aranguez I , Luft FC , Ramos MP , Gollasch M , Fernandez Alfonso MS . Perivascular adipose tissue and mesenteric vascular function in spontaneously hypertensive rats. Arterioscler Thromb Vasc Biol 26: 1297‐1302, 2006.
 108. Gao YJ , Holloway AC , Su LY , Takemori K , Lu C , Lee RM . Effects of fetal and neonatal exposure to nicotine on blood pressure and perivascular adipose tissue function in adult life. Eur J Pharmacol 590: 264‐268, 2008.
 109. Gao YJ , Holloway AC , Zeng ZH , Lim GE , Petrik JJ , Foster WG , Lee RM . Prenatal exposure to nicotine causes postnatal obesity and altered perivascular adipose tissue function. Obes Res 13: 687‐692, 2005.
 110. Gao YJ , Lu C , Su LY , Sharma AM , Lee RM . Modulation of vascular function by perivascular adipose tissue: the role of endothelium and hydrogen peroxide. Br J Pharmacol 151: 323‐331, 2007.
 111. Gao YJ , Takemori K , Su LY , An WS , Lu C , Sharma AM , Lee RM . Perivascular adipose tissue promotes vasoconstriction: the role of superoxide anion. Cardiovasc Res 71: 363‐373, 2006.
 112. Gao YJ , Zeng ZH , Teoh K , Sharma AM , Abouzahr L , Cybulsky I , Lamy A , Semelhago L , Lee RM . Perivascular adipose tissue modulates vascular function in the human internal thoracic artery. J Thorac Cardiovasc Surg 130: 1130‐1136, 2005.
 113. Gealekman O , Gurav K , Chouinard M , Straubhaar J , Thompson M , Malkani S , Hartigan C , Corvera S . Control of adipose tissue expandability in response to high fat diet by the insulin‐like growth factor‐binding protein‐4. J Biol Chem 289: 18327‐18338, 2014.
 114. Geller DA , de Vera ME , Russell DA , Shapiro RA , Nussler AK , Simmons RL , Billiar TR . A central role for IL‐1 beta in the in vitro and in vivo regulation of hepatic inducible nitric oxide synthase. IL‐1 beta induces hepatic nitric oxide synthesis. J Immunol 155: 4890‐4898, 1995.
 115. Gentile MT , Vecchione C , Marino G , Aretini A , Di Pardo A , Antenucci G , Maffei A , Cifelli G , Iorio L , Landolfi A , Frati G , Lembo G . Resistin impairs insulin‐evoked vasodilation. Diabetes 57: 577‐583, 2008.
 116. Gesta S , Bluher M , Yamamoto Y , Norris AW , Berndt J , Kralisch S , Boucher J , Lewis C , Kahn CR . Evidence for a role of developmental genes in the origin of obesity and body fat distribution. Proc Natl Acad Sci U S A 103: 6676‐6681, 2006.
 117. Gil‐Ortega M , Condezo‐Hoyos L , Garcia‐Prieto CF , Arribas SM , Gonzalez MC , Aranguez I , Ruiz‐Gayo M , Somoza B , Fernandez‐Alfonso MS . Imbalance between pro and anti‐oxidant mechanisms in perivascular adipose tissue aggravates long‐term high‐fat diet‐derived endothelial dysfunction. PloS One 9: e95312, 2014.
 118. Gil‐Ortega M , Martin‐Ramos M , Arribas SM , Gonzalez MC , Aranguez I , Ruiz‐Gayo M , Somoza B , Fernandez‐Alfonso MS . Arterial stiffness is associated with adipokine dysregulation in non‐hypertensive obese mice. Vascul Pharmacol 77: 38‐47, 2016.
 119. Gil‐Ortega M , Somoza B , Huang Y , Gollasch M , Fernandez‐Alfonso MS . Regional differences in perivascular adipose tissue impacting vascular homeostasis. Trends Endocrinol Metab 26: 367‐375, 2015.
 120. Gil‐Ortega M , Stucchi P , Guzman‐Ruiz R , Cano V , Arribas S , Gonzalez MC , Ruiz‐Gayo M , Fernandez‐Alfonso MS , Somoza B . Adaptative nitric oxide overproduction in perivascular adipose tissue during early diet‐induced obesity. Endocrinology 151: 3299‐3306, 2010.
 121. Gimble JM , Katz AJ , Bunnell BA . Adipose‐derived stem cells for regenerative medicine. Circ Res 100: 1249‐1260, 2007.
 122. Gollasch M . Adipose‐vascular coupling and potential therapeutics. Annu Rev Pharmacol Toxicol 57: 417‐436, 2016.
 123. Gollasch M. Vasodilator signals from perivascular adipose tissue. Br J Pharmacol 165: 633‐642, 2012.
 124. Goodpaster BH , Delany JP , Otto AD , Kuller L , Vockley J , South‐Paul JE , Thomas SB , Brown J , McTigue K , Hames KC , Lang W , Jakicic JM . Effects of diet and physical activity interventions on weight loss and cardiometabolic risk factors in severely obese adults: A randomized trial. Jama 304: 1795‐1802, 2010.
 125. Gorter PM , de Vos AM , van der Graaf Y , Stella PR , Doevendans PA , Meijs MF , Prokop M , Visseren FL . Relation of epicardial and pericoronary fat to coronary atherosclerosis and coronary artery calcium in patients undergoing coronary angiography. Am J Cardiol 102: 380‐385, 2008.
 126. Gossl M , Herrmann J , Tang H , Versari D , Galili O , Mannheim D , Rajkumar SV , Lerman LO , Lerman A . Prevention of vasa vasorum neovascularization attenuates early neointima formation in experimental hypercholesterolemia. Basic Res Cardiol 104: 695‐706, 2009.
 127. Grassi G. Sympathetic neural activity in hypertension and related diseases. Am J Hypertens 23: 1052‐1060, 2010.
 128. Grassi G , Seravalle G , Quarti‐Trevano F , Mineo C , Lonati L , Facchetti R , Mancia G . Reinforcement of the adrenergic overdrive in the metabolic syndrome complicated by obstructive sleep apnea. J Hypertens 28: 1313‐1320, 2010.
 129. Greenstein AS , Khavandi K , Withers SB , Sonoyama K , Clancy O , Jeziorska M , Laing I , Yates AP , Pemberton PW , Malik RA , Heagerty AM . Local inflammation and hypoxia abolish the protective anticontractile properties of perivascular fat in obese patients. Circulation 119: 1661‐1670, 2009.
 130. Gregor MF , Hotamisligil GS. Inflammatory mechanisms in obesity. Annu Rev Immunol 29: 415‐445, 2011.
 131. Grossman C , Bornstein G , Leibowitz A , Ben‐Zvi I , Grossman E . Effect of tumor necrosis factor‐alpha inhibitors on ambulatory 24‐h blood pressure. Blood Press 26: 24‐29, 2017.
 132. Grover TR , Zenge JP , Parker TA , Abman SH . Vascular endothelial growth factor causes pulmonary vasodilation through activation of the phosphatidylinositol‐3‐kinase‐nitric oxide pathway in the late‐gestation ovine fetus. Pediatr Res 52: 907‐912, 2002.
 133. Gu P , Xu A. Interplay between adipose tissue and blood vessels in obesity and vascular dysfunction. Rev Endocr Metab Disord 14: 49‐58, 2013.
 134. Gupta RK , Mepani RJ , Kleiner S , Lo JC , Khandekar MJ , Cohen P , Frontini A , Bhowmick DC , Ye L , Cinti S , Spiegelman BM . Zfp423 expression identifies committed preadipocytes and localizes to adipose endothelial and perivascular cells. Cell Metab 15: 230‐239, 2012.
 135. Guthrie JR , Dennerstein L , Taffe JR , Ebeling PR , Randolph JF , Burger HG , Wark JD . Central abdominal fat and endogenous hormones during the menopausal transition. Fertil Steril 79: 1335‐1340, 2003.
 136. Habata Y , Fujii R , Hosoya M , Fukusumi S , Kawamata Y , Hinuma S , Kitada C , Nishizawa N , Murosaki S , Kurokawa T , Onda H , Tatemoto K , Fujino M . Apelin, the natural ligand of the orphan receptor APJ, is abundantly secreted in the colostrum. Biochim Biophys Acta 1452: 25‐35, 1999.
 137. Halberg N , Khan T , Trujillo ME , Wernstedt‐Asterholm I , Attie AD , Sherwani S , Wang ZV , Landskroner‐Eiger S , Dineen S , Magalang UJ , Brekken RA , Scherer PE . Hypoxia‐inducible factor 1alpha induces fibrosis and insulin resistance in white adipose tissue. Mol Cell Biol 29: 4467‐4483, 2009.
 138. Hariya N , Mochizuki K , Inoue S , Morioka K , Shimada M , Okuda T , Goda T . Insulin resistance in SHR/NDmc‐cp rats correlates with enlarged perivascular adipocytes and endothelial cell dysfunction in skeletal muscle. J Nutr Sci Vitaminol (Tokyo) 60: 52‐59, 2014.
 139. Hasdai D , Nielsen MF , Rizza RA , Holmes DR, Jr. , Richardson DM , Cohen P , Lerman A . Attenuated in vitro coronary arteriolar vasorelaxation to insulin‐like growth factor I in experimental hypercholesterolemia. Hypertension 34: 89‐95, 1999.
 140. Hasdai D , Rizza RA , Holmes DR, Jr. , Richardson DM , Cohen P , Lerman A . Insulin and insulin‐like growth factor‐I cause coronary vasorelaxation in vitro. Hypertension 32: 228‐234, 1998.
 141. Hattori Y , Suzuki M , Hattori S , Kasai K . Globular adiponectin upregulates nitric oxide production in vascular endothelial cells. Diabetologia 46: 1543‐1549, 2003.
 142. Herbert MK , Holzer P. Interleukin‐1 beta enhances capsaicin‐induced neurogenic vasodilatation in the rat skin. Br J Pharmacol 111: 681‐686, 1994.
 143. Hertzel AV , Bernlohr DA. Regulation of adipocyte gene expression by polyunsaturated fatty acids. Mol Cell Biochem 188: 33‐39, 1998.
 144. Hirsch E , Katanaev VL , Garlanda C , Azzolino O , Pirola L , Silengo L , Sozzani S , Mantovani A , Altruda F , Wymann MP . Central role for G protein‐coupled phosphoinositide 3‐kinase gamma in inflammation. Science 287: 1049‐1053, 2000.
 145. Hocking S , Samocha‐Bonet D , Milner KL , Greenfield JR , Chisholm DJ . Adiposity and insulin resistance in humans: The role of the different tissue and cellular lipid depots. Endocr Rev 34: 463‐500, 2013.
 146. Hognogi LD , Simiti LV. The cardiovascular impact of visfatin—an inflammation predictor biomarker in metabolic syndrome. Clujul Med 89: 322‐326, 2016.
 147. Holmes DI , Zachary I. The vascular endothelial growth factor (VEGF) family: Angiogenic factors in health and disease. Genome Biol 6: 209, 2005.
 148. Hong K , Lee S , Li R , Yang Y , Tanner MA , Wu J , Hill MA . Adiponectin receptor agonist, AdipoRon, causes vasorelaxation predominantly via a direct smooth muscle action. Microcirculation 23: 207‐220, 2016.
 149. Horowitz JR , Rivard A , van der Zee R , Hariawala M , Sheriff DD , Esakof DD , Chaudhry GM , Symes JF , Isner JM . Vascular endothelial growth factor/vascular permeability factor produces nitric oxide‐dependent hypotension. Evidence for a maintenance role in quiescent adult endothelium. Arterioscler Thromb Vasc Biol 17: 2793‐2800, 1997.
 150. Hosogai N , Fukuhara A , Oshima K , Miyata Y , Tanaka S , Segawa K , Furukawa S , Tochino Y , Komuro R , Matsuda M , Shimomura I . Adipose tissue hypoxia in obesity and its impact on adipocytokine dysregulation. Diabetes 56: 901‐911, 2007.
 151. Hou N , Liu Y , Han F , Wang D , Hou X , Hou S , Sun X . Irisin improves perivascular adipose tissue dysfunction via regulation of the heme oxygenase‐1/adiponectin axis in diet‐induced obese mice. J Mol Cell Cardiol 99: 188‐196, 2016.
 152. Houben AJ , Eringa EC , Jonk AM , Serne EH , Smulders YM , Stehouwer CD . Perivascular fat and the microcirculation: Relevance to insulin resistance, diabetes, and cardiovascular disease. Curr Cardiovasc Risk Rep 6: 80‐90, 2012.
 153. Huang F , Lezama MA , Ontiveros JA , Bravo G , Villafana S , del‐Rio‐Navarro BE , Hong E . Effect of losartan on vascular function in fructose‐fed rats: The role of perivascular adipose tissue. Clin Exp Hypertens 32: 98‐104, 2010.
 154. Huh JY , Panagiotou G , Mougios V , Brinkoetter M , Vamvini MT , Schneider BE , Mantzoros CS . FNDC5 and irisin in humans: I. Predictors of circulating concentrations in serum and plasma and II. mRNA expression and circulating concentrations in response to weight loss and exercise. Metabolism 61: 1725‐1738, 2012.
 155. Iacobellis G. Epicardial adipose tissue in endocrine and metabolic diseases. Endocrine 46: 8‐15, 2014.
 156. Iacobellis G. Local and systemic effects of the multifaceted epicardial adipose tissue depot. Nat Rev Endocrinol 11: 363‐371, 2015.
 157. Iacobellis G , Gao YJ , Sharma AM . Do cardiac and perivascular adipose tissue play a role in atherosclerosis? Curr Diab Reps 8: 20‐24, 2008.
 158. Iacobellis G , Leonetti F , Singh N , A MS . Relationship of epicardial adipose tissue with atrial dimensions and diastolic function in morbidly obese subjects. Int J Cardiol 115: 272‐273, 2007.
 159. Iacobellis G , Pistilli D , Gucciardo M , Leonetti F , Miraldi F , Brancaccio G , Gallo P , di Gioia CR . Adiponectin expression in human epicardial adipose tissue in vivo is lower in patients with coronary artery disease. Cytokine 29: 251‐255, 2005.
 160. Iacobellis G , Ribaudo MC , Assael F , Vecci E , Tiberti C , Zappaterreno A , Di Mario U , Leonetti F . Echocardiographic epicardial adipose tissue is related to anthropometric and clinical parameters of metabolic syndrome: A new indicator of cardiovascular risk. J Clin Endocrinol Metab 88: 5163‐5168, 2003.
 161. Iacobellis G , Ribaudo MC , Zappaterreno A , Iannucci CV , Leonetti F . Relation between epicardial adipose tissue and left ventricular mass. Am J Cardiol 94: 1084‐1087, 2004.
 162. Imai J , Katagiri H , Yamada T , Ishigaki Y , Ogihara T , Uno K , Hasegawa Y , Gao J , Ishihara H , Sasano H , Oka Y . Cold exposure suppresses serum adiponectin levels through sympathetic nerve activation in mice. Obesity 14: 1132‐1141, 2006.
 163. Ishida J , Hashimoto T , Hashimoto Y , Nishiwaki S , Iguchi T , Harada S , Sugaya T , Matsuzaki H , Yamamoto R , Shiota N , Okunishi H , Kihara M , Umemura S , Sugiyama F , Yagami K , Kasuya Y , Mochizuki N , Fukamizu A . Regulatory roles for APJ, a seven‐transmembrane receptor related to angiotensin‐type 1 receptor in blood pressure in vivo. J Biol Chem 279: 26274‐26279, 2004.
 164. Ishii T , Asuwa N , Masuda S , Ishikawa Y . The effects of a myocardial bridge on coronary atherosclerosis and ischaemia. J Pathol 185: 4‐9, 1998.
 165. Ishikawa Y , Akasaka Y , Ito K , Akishima Y , Kimura M , Kiguchi H , Fujimoto A , Ishii T . Significance of anatomical properties of myocardial bridge on atherosclerosis evolution in the left anterior descending coronary artery. Atherosclerosis 186: 380‐389, 2006.
 166. Iwen KA , Wenzel ET , Ott V , Perwitz N , Wellhoner P , Lehnert H , Dodt C , Klein J . Cold‐induced alteration of adipokine profile in humans. Metabolism 60: 430‐437, 2011.
 167. Izhar U , Hasdai D , Richardson DM , Cohen P , Lerman A . Insulin and insulin‐like growth factor‐I cause vasorelaxation in human vessels in vitro. Coron Artery Dis 11: 69‐76, 2000.
 168. Janssen I , Powell LH , Jasielec MS , Kazlauskaite R . Covariation of change in bioavailable testosterone and adiposity in midlife women. Obesity 23: 488‐494, 2015.
 169. Japp AG , Cruden NL , Amer DA , Li VK , Goudie EB , Johnston NR , Sharma S , Neilson I , Webb DJ , Megson IL , Flapan AD , Newby DE . Vascular effects of apelin in vivo in man. J Am Coll Cardiol 52: 908‐913, 2008.
 170. Japp AG , Cruden NL , Barnes G , van Gemeren N , Mathews J , Adamson J , Johnston NR , Denvir MA , Megson IL , Flapan AD , Newby DE . Acute cardiovascular effects of apelin in humans: potential role in patients with chronic heart failure. Circulation 121: 1818‐1827, 2010.
 171. Jepps TA , Chadha PS , Davis AJ , Harhun MI , Cockerill GW , Olesen SP , Hansen RS , Greenwood IA . Downregulation of Kv7.4 channel activity in primary and secondary hypertension. Circulation 124: 602‐611, 2011.
 172. Jeremic N , Chaturvedi P , Tyagi SC . Browning of white fat: Novel insight into factors, mechanisms, and therapeutics. J Cell Physiol 232: 61‐68, 2017.
 173. Jia YX , Lu ZF , Zhang J , Pan CS , Yang JH , Zhao J , Yu F , Duan XH , Tang CS , Qi YF . Apelin activates L‐arginine/nitric oxide synthase/nitric oxide pathway in rat aortas. Peptides 28: 2023‐2029, 2007.
 174. Jiang M , Wan F , Wang F , Wu Q . Irisin relaxes mouse mesenteric arteries through endothelium‐dependent and endothelium‐independent mechanisms. Biochem Biophys Res Commun 468: 832‐836, 2015.
 175. Johns DG , Webb RC. TNF‐alpha‐induced endothelium‐independent vasodilation: A role for phospholipase A2‐dependent ceramide signaling. Am J Physiol 275: H1592‐H1598, 1998.
 176. Junquero DC , Schini VB , Scott‐Burden T , Vanhoutte PM . Enhanced production of nitric oxide in aortae from spontaneously hypertensive rats by interleukin‐1 beta. Am J Hypertens 6: 602‐610, 1993.
 177. Kagiwada K , Chida D , Sakatani T , Asano M , Nambu A , Kakuta S , Iwakura Y . Interleukin (IL)‐6, but not IL‐1, induction in the brain downstream of cyclooxygenase‐2 is essential for the induction of febrile response against peripheral IL‐1alpha. Endocrinology 145: 5044‐5048, 2004.
 178. Kagiyama S , Fukuhara M , Matsumura K , Lin Y , Fujii K , Iida M . Central and peripheral cardiovascular actions of apelin in conscious rats. Regul Pept 125: 55‐59, 2005.
 179. Kangussu L , Guimaraes P , Nadu AP , Bader M , Santos R , Campagnole‐Santos M . Angiotensin‐(1‐7) infusion in the brain reduced blood pressure and cardiac hypertrophy in (mRen2)27 transgenic hypertensive rats (LB647). FASEB J 28: LB647, 2014.
 180. Karkkainen MJ , Petrova TV. Vascular endothelial growth factor receptors in the regulation of angiogenesis and lymphangiogenesis. Oncogene 19: 5598‐5605, 2000.
 181. Kataoka Y , Shibata R , Ohashi K , Kambara T , Enomoto T , Uemura Y , Ogura Y , Yuasa D , Matsuo K , Nagata T , Oba T , Yasukawa H , Numaguchi Y , Sone T , Murohara T , Ouchi N . Omentin prevents myocardial ischemic injury through AMP‐activated protein kinase‐ and Akt‐dependent mechanisms. J Am Coll Cardiol 63: 2722‐2733, 2014.
 182. Kazama K , Okada M , Yamawaki H . A novel adipocytokine, omentin, inhibits monocrotaline‐induced pulmonary arterial hypertension in rats. Biochem Biophys Res Commun 452: 142‐146, 2014.
 183. Kenny D , McCarthy‐Kenny G , Pelc LR , Cheung HS , Brooks HL , Warltier DC . Vasodilator actions of interleukin‐1 in the canine coronary circulation. Basic Res Cardiol 85: 279‐284, 1990.
 184. Ketonen J , Shi J , Martonen E , Mervaala E . Periadventitial adipose tissue promotes endothelial dysfunction via oxidative stress in diet‐induced obese C57Bl/6 mice. Circ J 74: 1479‐1487, 2010.
 185. Klouche M , Bhakdi S , Hemmes M , Rose‐John S . Novel path to activation of vascular smooth muscle cells: Up‐regulation of gp130 creates an autocrine activation loop by IL‐6 and its soluble receptor. J Immunol 163: 4583‐4589, 1999.
 186. Kobayashi T , Kamata K. Modulation by hydrogen peroxide of noradrenaline‐induced contraction in aorta from streptozotocin‐induced diabetic rat. Eur J Pharmacol 441: 83‐89, 2002.
 187. Kohn C , Schleifenbaum J , Szijarto IA , Marko L , Dubrovska G , Huang Y , Gollasch M . Differential effects of cystathionine‐gamma‐lyase‐dependent vasodilatory H2S in periadventitial vasoregulation of rat and mouse aortas. PloS One 7: e41951, 2012.
 188. Korner A , Garten A , Bluher M , Tauscher R , Kratzsch J , Kiess W . Molecular characteristics of serum visfatin and differential detection by immunoassays. J Clin Endocrinol Metab 92: 4783‐4791, 2007.
 189. Kortelainen ML , Pelletier G , Ricquier D , Bukowiecki LJ . Immunohistochemical detection of human brown adipose tissue uncoupling protein in an autopsy series. J Histochem Cytochem 41: 759‐764, 1993.
 190. Kougias P , Chai H , Lin PH , Lumsden AB , Yao Q , Chen C . Adipocyte‐derived cytokine resistin causes endothelial dysfunction of porcine coronary arteries. J Vasc Surg 41: 691‐698, 2005.
 191. Kurdiova T , Balaz M , Vician M , Maderova D , Vlcek M , Valkovic L , Srbecky M , Imrich R , Kyselovicova O , Belan V , Jelok I , Wolfrum C , Klimes I , Krssak M , Zemkova E , Gasperikova D , Ukropec J , Ukropcova B . Effects of obesity, diabetes and exercise on Fndc5 gene expression and irisin release in human skeletal muscle and adipose tissue: In vivo and in vitro studies. J Physiol 592: 1091‐1107, 2014.
 192. Kurobe H , Hirata Y , Matsuoka Y , Sugasawa N , Higashida M , Nakayama T , Maxfield MW , Yoshida Y , Shimabukuro M , Kitagawa T , Sata M . Protective effects of selective mineralocorticoid receptor antagonist against aortic aneurysm progression in a novel murine model. J Surg Res 185: 455‐462, 2013.
 193. Kwon HM , Sangiorgi G , Ritman EL , Lerman A , McKenna C , Virmani R , Edwards WD , Holmes DR , Schwartz RS . Adventitial vasa vasorum in balloon‐injured coronary arteries: Visualization and quantitation by a microscopic three‐dimensional computed tomography technique. J Am Coll Cardiol 32: 2072‐2079, 1998.
 194. Laiguillon MC , Houard X , Bougault C , Gosset M , Nourissat G , Sautet A , Jacques C , Berenbaum F , Sellam J . Expression and function of visfatin (Nampt), an adipokine‐enzyme involved in inflammatory pathways of osteoarthritis. Arthritis Res Ther 16: R38, 2014.
 195. Langenberg C , Bergstrom J , Scheidt‐Nave C , Pfeilschifter J , Barrett‐Connor E . Cardiovascular death and the metabolic syndrome: Role of adiposity‐signaling hormones and inflammatory markers. Diabetes Care 29: 1363‐1369, 2006.
 196. Lebona GT. The presence of paraganglia in the human ascending aortic fold: Histological and ultrastructural studies. J Anat 183(Pt 1): 35‐41, 1993.
 197. Lee DL , Leite R , Fleming C , Pollock JS , Webb RC , Brands MW . Hypertensive response to acute stress is attenuated in interleukin‐6 knockout mice. Hypertension 44: 259‐263, 2004.
 198. Lee DL , Sturgis LC , Labazi H , Osborne JB, Jr. , Fleming C , Pollock JS , Manhiani M , Imig JD , Brands MW . Angiotensin II hypertension is attenuated in interleukin‐6 knockout mice. J Physiol Heart Circ Physiol 290: H935‐H940, 2006.
 199. Lee MH , Chen SJ , Tsao CM , Wu CC . Perivascular adipose tissue inhibits endothelial function of rat aortas via caveolin‐1. PloS One 9: e99947, 2014.
 200. Lee RM , Bader M , Alenina N , Santos RA , Gao YJ , Lu C . Mas receptors in modulating relaxation induced by perivascular adipose tissue. Life Sci 89: 467‐472, 2011.
 201. Lee RM , Ding L , Lu C , Su LY , Gao YJ . Alteration of perivascular adipose tissue function in angiotensin II‐induced hypertension. Can J Physiol Pharmacol 87: 944‐953, 2009.
 202. Lee RM , Lu C , Su LY , Gao YJ . Endothelium‐dependent relaxation factor released by perivascular adipose tissue. J Hypertens 27: 782‐790, 2009.
 203. Lee YC , Chang HH , Chiang CL , Liu CH , Yeh JI , Chen MF , Chen PY , Kuo JS , Lee TJ . Role of perivascular adipose tissue‐derived methyl palmitate in vascular tone regulation and pathogenesis of hypertension. Circulation 124: 1160‐1171, 2011.
 204. Lee YC , Chang HH , Liu CH , Chen MF , Chen PY , Kuo JS , Lee TJ . Methyl palmitate: A potent vasodilator released in the retina. Invest Ophthalmol Vis Sci 51: 4746‐4753, 2010.
 205. Lehman SJ , Massaro JM , Schlett CL , O'Donnell CJ , Hoffmann U , Fox CS . Peri‐aortic fat, cardiovascular disease risk factors, and aortic calcification: The Framingham Heart Study. Atherosclerosis 210: 656‐661, 2010.
 206. Lembo G , Rockman HA , Hunter JJ , Steinmetz H , Koch WJ , Ma L , Prinz MP , Ross J, Jr. , Chien KR , Powell‐Braxton L . Elevated blood pressure and enhanced myocardial contractility in mice with severe IGF‐1 deficiency. J Clin Invest 98: 2648‐2655, 1996.
 207. Lembo G , Vecchione C , Fratta L , Marino G , Trimarco V , d'Amati G , Trimarco B . Leptin induces direct vasodilation through distinct endothelial mechanisms. Diabetes 49: 293‐297, 2000.
 208. Li X , Eriksson U. Novel VEGF family members: VEGF‐B, VEGF‐C and VEGF‐D. Int J Biochem Cell Biol 33: 421‐426, 2001.
 209. Lin YY , Lee SD , Su CT , Cheng TL , Yang AL . Long‐term treadmill training ameliorates endothelium‐dependent vasorelaxation mediated by insulin and insulin‐like growth factor‐1 in hypertension. J Appl Physiol 119: 663‐669, 2015.
 210. Liu C , Su T , Li F , Li L , Qin X , Pan W , Feng F , Chen F , Liao D , Chen L . PI3K/Akt signaling transduction pathway is involved in rat vascular smooth muscle cell proliferation induced by apelin‐13. Acta Biochim Biophy Sin 42: 396‐402, 2010.
 211. Liu J , Fox CS , Hickson D , Sarpong D , Ekunwe L , May WD , Hundley GW , Carr JJ , Taylor HA . Pericardial adipose tissue, atherosclerosis, and cardiovascular disease risk factors: The Jackson heart study. Diabetes Care 33: 1635‐1639, 2010.
 212. Liu P , Feng J , Kong F , Lu Q , Xu H , Meng J , Jiang Y . Gax inhibits perivascular preadipocyte biofunction mediated by IGF‐1 induced FAK/Pyk2 and ERK2 cooperative pathways. Cell Signal 26: 3036‐3045, 2014.
 213. Lohn M , Dubrovska G , Lauterbach B , Luft FC , Gollasch M , Sharma AM . Periadventitial fat releases a vascular relaxing factor. FASEB J 16: 1057‐1063, 2002.
 214. Loughrey JP , Laffey JG , Moore BJ , Lynch F , Boylan JF , McLoughlin P . Interleukin‐1 beta rapidly inhibits aortic endothelium‐dependent relaxation by a DNA transcription‐dependent mechanism. Crit Care Med 31: 910‐915, 2003.
 215. Lu C , Su LY , Lee RM , Gao YJ . Alterations in perivascular adipose tissue structure and function in hypertension. Eur J Pharmacol 656: 68‐73, 2011.
 216. Lu C , Su LY , Lee RM , Gao YJ . Mechanisms for perivascular adipose tissue‐mediated potentiation of vascular contraction to perivascular neuronal stimulation: The role of adipocyte‐derived angiotensin II. Eur J Pharmacol 634: 107‐112, 2010.
 217. Lu C , Zhao AX , Gao YJ , Lee RM . Modulation of vein function by perivascular adipose tissue. Eur J Pharmacol 657: 111‐116, 2011.
 218. Lu MT , Park J , Ghemigian K , Mayrhofer T , Puchner SB , Liu T , Fleg JL , Udelson JE , Truong QA , Ferencik M , Hoffmann U . Epicardial and paracardial adipose tissue volume and attenuation—association with high‐risk coronary plaque on computed tomographic angiography in the ROMICAT II trial. Atherosclerosis 251: 47‐54, 2016.
 219. Lynch FM , Withers SB , Yao Z , Werner ME , Edwards G , Weston AH , Heagerty AM . Perivascular adipose tissue‐derived adiponectin activates BK(Ca) channels to induce anticontractile responses. J Physiol Heart Circ Physiol 304: H786‐H795, 2013.
 220. Ma L , Ma S , He H , Yang D , Chen X , Luo Z , Liu D , Zhu Z . Perivascular fat‐mediated vascular dysfunction and remodeling through the AMPK/mTOR pathway in high‐fat diet‐induced obese rats. Hypertens Res 33: 446‐453, 2010.
 221. Maenhaut N , Boydens C , Van de Voorde J . Hypoxia enhances the relaxing influence of perivascular adipose tissue in isolated mice aorta. Eur J Pharmacol 641: 207‐212, 2010.
 222. Maenhaut N , Van de Voorde J . Regulation of vascular tone by adipocytes. BMC medicine 9: 25, 2011.
 223. Mahabadi AA , Berg MH , Lehmann N , Kalsch H , Bauer M , Kara K , Dragano N , Moebus S , Jockel KH , Erbel R , Mohlenkamp S . Association of epicardial fat with cardiovascular risk factors and incident myocardial infarction in the general population: The Heinz Nixdorf Recall Study. J Am Coll Cardiol 61: 1388‐1395, 2013.
 224. Mahabadi AA , Massaro JM , Rosito GA , Levy D , Murabito JM , Wolf PA , O'Donnell CJ , Fox CS , Hoffmann U . Association of pericardial fat, intrathoracic fat, and visceral abdominal fat with cardiovascular disease burden: The Framingham Heart Study. Eur Heart J 30: 850‐856, 2009.
 225. Malinowski M , Deja MA , Golba KS , Roleder T , Biernat J , Wos S . Perivascular tissue of internal thoracic artery releases potent nitric oxide and prostacyclin‐independent anticontractile factor. Eur J Cardiothorac Surg 33: 225‐231, 2008.
 226. Manka D , Chatterjee TK , Stoll LL , Basford JE , Konaniah ES , Srinivasan R , Bogdanov VY , Tang Y , Blomkalns AL , Hui DY , Weintraub NL . Transplanted perivascular adipose tissue accelerates injury‐induced neointimal hyperplasia: Role of monocyte chemoattractant protein‐1. Arterioscler Thromb Vasc Biol 34: 1723‐1730, 2014.
 227. Marceau F , Petitclerc E , DeBlois D , Pradelles P , Poubelle PE . Human interleukin‐1 induces a rapid relaxation of the rabbit isolated mesenteric artery. Br J Pharmacol 103: 1367‐1372, 1991.
 228. Marchesi C , Ebrahimian T , Angulo O , Paradis P , Schiffrin EL . Endothelial nitric oxide synthase uncoupling and perivascular adipose oxidative stress and inflammation contribute to vascular dysfunction in a rodent model of metabolic syndrome. Hypertension 54: 1384‐1392, 2009.
 229. Margaritis M , Antonopoulos AS , Digby J , Lee R , Reilly S , Coutinho P , Shirodaria C , Sayeed R , Petrou M , De Silva R , Jalilzadeh S , Demosthenous M , Bakogiannis C , Tousoulis D , Stefanadis C , Choudhury RP , Casadei B , Channon KM , Antoniades C . Interactions between vascular wall and perivascular adipose tissue reveal novel roles for adiponectin in the regulation of endothelial nitric oxide synthase function in human vessels. Circulation 127: 2209‐2221, 2013.
 230. Marko L , Szijarto IA , Filipovic MR , Kassmann M , Balogh A , Park JK , Przybyl L , N'Diaye G , Kramer S , Anders J , Ishii I , Muller DN , Gollasch M . Role of cystathionine gamma‐lyase in immediate renal impairment and inflammatory response in acute ischemic kidney injury. Sci Rep 6: 27517, 2016.
 231. Martelli A , Testai L , Breschi MC , Lawson K , McKay NG , Miceli F , Taglialatela M , Calderone V . Vasorelaxation by hydrogen sulphide involves activation of Kv7 potassium channels. Pharmacol Res 70: 27‐34, 2013.
 232. Marumo T , Schini‐Kerth VB , Busse R . Vascular endothelial growth factor activates nuclear factor‐kappaB and induces monocyte chemoattractant protein‐1 in bovine retinal endothelial cells. Diabetes 48: 1131‐1137, 1999.
 233. Matoba T , Shimokawa H , Nakashima M , Hirakawa Y , Mukai Y , Hirano K , Kanaide H , Takeshita A . Hydrogen peroxide is an endothelium‐derived hyperpolarizing factor in mice. J Clin Invest 106: 1521‐1530, 2000.
 234. Matter CM , Stein MA. A dual role of CD4+ T cells in adipose tissue? Circ Res 104: 928‐930, 2009.
 235. Matthias A , Richards SM , Dora KA , Clark MG , Colquhoun EQ . Characterization of perfused periaortic brown adipose tissue from the rat. Can J Physiol Pharmacol 72: 344‐352, 1994.
 236. Mauro CR , Ilonzo G , Nguyen BT , Yu P , Tao M , Gao I , Seidman MA , Nguyen LL , Ozaki CK . Attenuated adiposopathy in perivascular adipose tissue compared with subcutaneous human adipose tissue. Am J Surg 206: 241‐244, 2013.
 237. Mauro CR , Nguyen BT , Yu P , Tao M , Gao I , Seidman MA , Nguyen LL , Ozaki CK . Inflammatory “adiposopathy” in major amputation patients. Ann Vasc Surg 27: 346‐352, 2013.
 238. Mazurek T , Opolski G. Pericoronary adipose tissue: A novel therapeutic target in obesity‐related coronary atherosclerosis. J Am Coll Nutr 34: 244‐254, 2015.
 239. Mazurek T , Zhang L , Zalewski A , Mannion JD , Diehl JT , Arafat H , Sarov‐Blat L , O'Brien S , Keiper EA , Johnson AG , Martin J , Goldstein BJ , Shi Y . Human epicardial adipose tissue is a source of inflammatory mediators. Circulation 108: 2460‐2466, 2003.
 240. McCallum RW , Hamilton CA , Graham D , Jardine E , Connell JM , Dominiczak AF . Vascular responses to IGF‐I and insulin are impaired in aortae of hypertensive rats. J Hypertens 23: 351‐358, 2005.
 241. McCurdy CE , Klemm DJ. Adipose tissue insulin sensitivity and macrophage recruitment: Does PI3K pick the pathway? Adipocyte 2: 135‐142, 2013.
 242. McRae CR , Rao SP , Dunbar JC . Cardiovascular action of insulin‐like growth factor‐1 is not mediated by calcitonin gene‐related peptide neurons. Endocrine 19: 163‐167, 2002.
 243. McTernan PG , Kusminski CM , Kumar S . Resistin. Curr Opin Lipidol 17: 170‐175, 2006.
 244. Meijer RI , Bakker W , Alta CL , Sipkema P , Yudkin JS , Viollet B , Richter EA , Smulders YM , van Hinsbergh VW , Serne EH , Eringa EC . Perivascular adipose tissue control of insulin‐induced vasoreactivity in muscle is impaired in db/db mice. Diabetes 62: 590‐598, 2013.
 245. Meijer RI , Serne EH , Korkmaz HI , van der Peet DL , de Boer MP , Niessen HW , van Hinsbergh VW , Yudkin JS , Smulders YM , Eringa EC . Insulin‐induced changes in skeletal muscle microvascular perfusion are dependent upon perivascular adipose tissue in women. Diabetologia 58: 1907‐1915, 2015.
 246. Meijer RI , Serne EH , Smulders YM , van Hinsbergh VW , Yudkin JS , Eringa EC . Perivascular adipose tissue and its role in type 2 diabetes and cardiovascular disease. Curr Diab Reps 11: 211‐217, 2011.
 247. Melis A , Watts SW , Florian J , Klarr S , Webb RC . Insulin‐like growth factor inhibits vascular contraction to 5‐hydroxytryptamine: involvement of tyrosine phosphatase. Gen Pharmacol 34: 137‐145, 2000.
 248. Meyer MR , Fredette NC , Barton M , Prossnitz ER . Regulation of vascular smooth muscle tone by adipose‐derived contracting factor. PloS One 8: e79245, 2013.
 249. Miao CY , Li ZY. The role of perivascular adipose tissue in vascular smooth muscle cell growth. Br J Pharmacol 165: 643‐658, 2012.
 250. Minghini A , Britt LD , Hill MA . Interleukin‐1 and interleukin‐6 mediated skeletal muscle arteriolar vasodilation: In vitro versus in vivo studies. Shock 9: 210‐215, 1998.
 251. Moe KT , Naylynn TM , Yin NO , Khairunnisa K , Allen JC , Wong MC , Chin‐Dusting J , Wong P . Tumor necrosis factor‐alpha induces aortic intima‐media thickening via perivascular adipose tissue inflammation. J Vasc Res 50: 228‐237, 2013.
 252. Momin AU , Melikian N , Shah AM , Grieve DJ , Wheatcroft SB , John L , El Gamel A , Desai JB , Nelson T , Driver C , Sherwood RA , Kearney MT . Leptin is an endothelial‐independent vasodilator in humans with coronary artery disease: Evidence for tissue specificity of leptin resistance. Eur Heart J 27: 2294‐2299, 2006.
 253. Mori TA , Bao DQ , Burke V , Puddey IB , Beilin LJ . Docosahexaenoic acid but not eicosapentaenoic acid lowers ambulatory blood pressure and heart rate in humans. Hypertension 34: 253‐260, 1999.
 254. Murakami Y , Nagatani Y , Takahashi M , Ikeda M , Miyazawa I , Morino K , Ohkubo T , Maegawa H , Nitta N , Sakai H , Nota H , Ushio N , Murata K . Renal sinus fat volume on computed tomography in middle‐aged patients at risk for cardiovascular disease and its association with coronary artery calcification. Atherosclerosis 246: 374‐381, 2016.
 255. Nagaraj N , Matthews KA , Shields KJ , Barinas‐Mitchell E , Budoff MJ , El Khoudary SR . Complement proteins and arterial calcification in middle aged women: Cross‐sectional effect of cardiovascular fat. The SWAN Cardiovascular Fat Ancillary Study. Atherosclerosis 243: 533‐539, 2015.
 256. Nam HJ , Jung IH , Kim J , Kim JH , Suh J , Kim HS , Kim HK , Jung YJ , Kang JW , Lee S . Association between brachial‐ankle pulse wave velocity and occult coronary artery disease detected by multi‐detector computed tomography. Int J Cardiol 157: 227‐232, 2012.
 257. Nielsen G , Wandall‐Frostholm C , Sadda V , Olivan‐Viguera A , Lloyd EE , Bryan RM, Jr. , Simonsen U , Kohler R . Alterations of N‐3 polyunsaturated fatty acid‐activated K2P channels in hypoxia‐induced pulmo-nary hypertension. Basic Clin Pharmacol Toxicol 113: 250‐258, 2013.
 258. Noblet JN , Owen MK , Goodwill AG , Sassoon DJ , Tune JD . Lean and obese coronary perivascular adipose tissue impairs vasodilation via differential inhibition of vascular smooth muscle K+ channels. Arterioscler Thromb Vasc Biol 35: 1393‐1400, 2015.
 259. Ohkawa F , Ikeda U , Kawasaki K , Kusano E , Igarashi M , Shimada K . Inhibitory effect of interleukin‐6 on vascular smooth muscle contraction. Am J Physiol 266: H898‐H902, 1994.
 260. Oltman CL , Kane NL , Gutterman DD , Bar RS , Dellsperger KC . Mechanism of coronary vasodilation to insulin and insulin‐like growth factor I is dependent on vessel size. Am J Physiol Endocrinol Metab 279: E176‐E181, 2000.
 261. Omae T , Nagaoka T , Tanano I , Yoshida A . Adiponectin‐induced dilation of isolated porcine retinal arterioles via production of nitric oxide from endothelial cells. Invest Ophthalmol Vis Sci 54: 4586‐4594, 2013.
 262. Omar A , Chatterjee TK , Tang Y , Hui DY , Weintraub NL . Proinflammatory phenotype of perivascular adipocytes. Arterioscler Thromb Vasc Biol 34: 1631‐1636, 2014.
 263. Ouchi N , Ohishi M , Kihara S , Funahashi T , Nakamura T , Nagaretani H , Kumada M , Ohashi K , Okamoto Y , Nishizawa H , Kishida K , Maeda N , Nagasawa A , Kobayashi H , Hiraoka H , Komai N , Kaibe M , Rakugi H , Ogihara T , Matsuzawa Y . Association of hypoadiponectinemia with impaired vasoreactivity. Hypertension 42: 231‐234, 2003.
 264. Ouwens DM , Sell H , Greulich S , Eckel J . The role of epicardial and perivascular adipose tissue in the pathophysiology of cardiovascular disease. J Cell Mol Med 14: 2223‐2234, 2010.
 265. Owen MK , Witzmann FA , McKenney ML , Lai X , Berwick ZC , Moberly SP , Alloosh M , Sturek M , Tune JD . Perivascular adipose tissue potentiates contraction of coronary vascular smooth muscle: Influence of obesity. Circulation 128: 9‐18, 2013.
 266. Ozen G , Topal G , Gomez I , Ghorreshi A , Boukais K , Benyahia C , Kanyinda L , Longrois D , Teskin O , Uydes‐Dogan BS , Norel X . Control of human vascular tone by prostanoids derived from perivascular adipose tissue. Prostaglandins Other Lipid Mediat 107: 13‐17, 2013.
 267. Padilla J , Jenkins NT , Vieira‐Potter VJ , Laughlin MH . Divergent phenotype of rat thoracic and abdominal perivascular adipose tissues. Am J Physiol Regul Integr Comp Physiol 304: R543‐R552, 2013.
 268. Pandolfi R , Barreira B , Moreno E , Lara‐Acedo V , Morales‐Cano D , Martinez‐Ramas A , de Olaiz Navarro B , Herrero R , Lorente JA , Cogolludo A , Perez‐Vizcaino F , Moreno L . Role of acid sphingomyelinase and IL‐6 as mediators of endotoxin‐induced pulmonary vascular dysfunction. Thorax 72: 460-471, 2017.
 269. Park SY , Kim KH , Seo KW , Bae JU , Kim YH , Lee SJ , Lee WS , Kim CD . Resistin derived from diabetic perivascular adipose tissue up‐regulates vascular expression of osteopontin via the AP‐1 signalling pathway. J Pathol 232: 87‐97, 2014.
 270. Pauletto P , Rattazzi M. Inflammation and hypertension: The search for a link. Nephrol Dial Transplant 21: 850‐853, 2006.
 271. Payne GA , Bohlen HG , Dincer UD , Borbouse L , Tune JD . Periadventitial adipose tissue impairs coronary endothelial function via PKC‐beta‐dependent phosphorylation of nitric oxide synthase. J Physiol Heart Circ Physiol 297: H460‐H465, 2009.
 272. Payne GA , Borbouse L , Bratz IN , Roell WC , Bohlen HG , Dick GM , Tune JD . Endogenous adipose‐derived factors diminish coronary endothelial function via inhibition of nitric oxide synthase. Microcirculation 15: 417‐426, 2008.
 273. Payne GA , Borbouse L , Kumar S , Neeb Z , Alloosh M , Sturek M , Tune JD . Epicardial perivascular adipose‐derived leptin exacerbates coronary endothelial dysfunction in metabolic syndrome via a protein kinase C‐beta pathway. Arterioscler Thromb Vasc Biol 30: 1711‐1717, 2010.
 274. Peterson KM , Aly A , Lerman A , Lerman LO , Rodriguez‐Porcel M . Improved survival of mesenchymal stromal cell after hypoxia preconditioning: Role of oxidative stress. Life Sci 88: 65‐73, 2011.
 275. Petitclerc E , Poubelle PE , Marceau F . Rapid protein synthesis and turnover is involved in interleukin‐1‐induced relaxation of the rabbit isolated mesenteric artery. Analysis of the arachidonate cascade. J Pharmacol Exp Ther 268: 1419‐1425, 1994.
 276. Picchi A , Gao X , Belmadani S , Potter BJ , Focardi M , Chilian WM , Zhang C . Tumor necrosis factor‐alpha induces endothelial dysfunction in the prediabetic metabolic syndrome. Circ Res 99: 69‐77, 2006.
 277. Pluger S , Faulhaber J , Furstenau M , Lohn M , Waldschutz R , Gollasch M , Haller H , Luft FC , Ehmke H , Pongs O . Mice with disrupted BK channel beta1 subunit gene feature abnormal Ca(2+) spark/STOC coupling and elevated blood pressure. Circ Res 87: E53‐E60, 2000.
 278. Police SB , Thatcher SE , Charnigo R , Daugherty A , Cassis LA . Obesity promotes inflammation in periaortic adipose tissue and angiotensin II‐induced abdominal aortic aneurysm formation. Arterioscler Thromb Vasc Biol 29: 1458‐1464, 2009.
 279. Prati F , Arbustini E , Labellarte A , Sommariva L , Pawlowski T , Manzoli A , Pagano A , Motolese M , Boccanelli A . Eccentric atherosclerotic plaques with positive remodelling have a pericardial distribution: A permissive role of epicardial fat? A three‐dimensional intravascular ultrasound study of left anterior descending artery lesions. Eur Heart J 24: 329‐336, 2003.
 280. Pravenec M , Mlejnek P , Zidek V , Landa V , Simakova M , Silhavy J , Strnad H , Eigner S , Eigner Henke K , Skop V , Malinska H , Trnovska J , Kazdova L , Drahota Z , Mracek T , Houstek J . Autocrine effects of transgenic resistin reduce palmitate and glucose oxidation in brown adipose tissue. Physiol Genomics 48: 420‐427, 2016.
 281. Purkayastha S , Zhang G , Cai D . Uncoupling the mechanisms of obesity and hypertension by targeting hypothalamic IKK‐beta and NF‐kappaB. Nat Med 17: 883‐887, 2011.
 282. Rabkin SW. Epicardial fat: Properties, function and relationship to obesity. Obes Rev 8: 253‐261, 2007.
 283. Radcliff K , Tang TB , Lim J , Zhang Z , Abedin M , Demer LL , Tintut Y . Insulin‐like growth factor‐I regulates proliferation and osteoblastic differentiation of calcifying vascular cells via extracellular signal‐regulated protein kinase and phosphatidylinositol 3‐kinase pathways. Circ Res 96: 398‐400, 2005.
 284. Rausch ME , Weisberg S , Vardhana P , Tortoriello DV . Obesity in C57BL/6J mice is characterized by adipose tissue hypoxia and cytotoxic T‐cell infiltration. Int J Obes 32: 451‐463, 2008.
 285. Rebolledo A , Rebolledo OR , Marra CA , Garcia ME , Roldan Palomo AR , Rimorini L , Gagliardino JJ . Early alterations in vascular contractility associated to changes in fatty acid composition and oxidative stress markers in perivascular adipose tissue. Cardiovasc Diabetol 9: 65, 2010.
 286. Rega G , Kaun C , Demyanets S , Pfaffenberger S , Rychli K , Hohensinner PJ , Kastl SP , Speidl WS , Weiss TW , Breuss JM , Furnkranz A , Uhrin P , Zaujec J , Zilberfarb V , Frey M , Roehle R , Maurer G , Huber K , Wojta J . Vascular endothelial growth factor is induced by the inflammatory cytokines interleukin‐6 and oncostatin m in human adipose tissue in vitro and in murine adipose tissue in vivo. Arterioscler Thromb Vasc Biol 27: 1587‐1595, 2007.
 287. Reynolds RM , Allan KM , Raja EA , Bhattacharya S , McNeill G , Hannaford PC , Sarwar N , Lee AJ , Bhattacharya S , Norman JE . Maternal obesity during pregnancy and premature mortality from cardiovascular event in adult offspring: follow‐up of 1 323 275 person years. Bmj 347: f4539, 2013.
 288. Ridker PM , Rifai N , Stampfer MJ , Hennekens CH . Plasma concentration of interleukin‐6 and the risk of future myocardial infarction among apparently healthy men. Circulation 101: 1767‐1772, 2000.
 289. Riedel K , Koellensperger E , Ryssel H , Riedel F , Goessler UR , Germann G , Kremer T . Abrogation of TGF‐beta by antisense oligonucleotides modulates expression of VEGF and increases angiogenic potential in isolated fibroblasts from radiated skin. Int J Mol Med 22: 473‐480, 2008.
 290. Rittig K , Dolderer JH , Balletshofer B , Machann J , Schick F , Meile T , Kuper M , Stock UA , Staiger H , Machicao F , Schaller HE , Konigsrainer A , Haring HU , Siegel‐Axel DI . The secretion pattern of perivascular fat cells is different from that of subcutaneous and visceral fat cells. Diabetologia 55: 1514‐1525, 2012.
 291. Rittig K , Staib K , Machann J , Bottcher M , Peter A , Schick F , Claussen C , Stefan N , Fritsche A , Haring HU , Balletshofer B . Perivascular fatty tissue at the brachial artery is linked to insulin resistance but not to local endothelial dysfunction. Diabetologia 51: 2093‐2099, 2008.
 292. Robert R , Chapelain B , Jean T , Neliat G . Interleukin‐1 impairs both vascular contraction and relaxation in rabbit isolated aorta. Biochem Biophys Res Commun 182: 733‐739, 1992.
 293. Rodriguez‐Martinez MA , Garcia‐Cohen EC , Baena AB , Gonzalez R , Salaices M , Marin J . Contractile responses elicited by hydrogen peroxide in aorta from normotensive and hypertensive rats. Endothelial modulation and mechanism involved. Br J Pharmacol 125: 1329‐1335, 1998.
 294. Rongvaux A , Galli M , Denanglaire S , Van Gool F , Dreze PL , Szpirer C , Bureau F , Andris F , Leo O . Nicotinamide phosphoribosyl transferase/pre‐B cell colony‐enhancing factor/visfatin is required for lymphocyte development and cellular resistance to genotoxic stress. J Immunol 181: 4685‐4695, 2008.
 295. Rosei CA , Withers SB , Belcaid L , De Ciuceis C , Rizzoni D , Heagerty AM . Blockade of the renin‐angiotensin system in small arteries and anticontractile function of perivascular adipose tissue. J Hypertens 33: 1039‐1045, 2015.
 296. Rosito GA , Massaro JM , Hoffmann U , Ruberg FL , Mahabadi AA , Vasan RS , O'Donnell CJ , Fox CS . Pericardial fat, visceral abdominal fat, cardiovascular disease risk factors, and vascular calcification in a community‐based sample: the Framingham Heart Study. Circulation 117: 605‐613, 2008.
 297. Roskoski R, Jr . ERK1/2 MAP kinases: Structure, function, and regulation. Pharmacol Res 66: 105‐143, 2012.
 298. Ruan CC , Zhu DL , Chen QZ , Chen J , Guo SJ , Li XD , Gao PJ . Perivascular adipose tissue‐derived complement 3 is required for adventitial fibroblast functions and adventitial remodeling in deoxycorticosterone acetate‐salt hypertensive rats. Arterioscler Thromb Vasc Biol 30: 2568‐2574, 2010.
 299. Sacks HS , Fain JN. Human epicardial adipose tissue: A review. Am Heart J 153: 907‐917, 2007.
 300. Saely CH , Leiherer A , Muendlein A , Vonbank A , Rein P , Geiger K , Malin C , Drexel H . Coronary patients with high plasma omentin are at a higher cardiovascular risk. Data Brief 6: 158‐161, 2016.
 301. Sahin AS , Bariskaner H , Gokbel H , Okudan N . The dual effects of leptin on aortic rings with and without endothelium isolated from streptozotocin‐induced diabetic rats. Methods Find Exp Clin Pharmacol 31: 325‐329, 2009.
 302. Salcedo A , Garijo J , Monge L , Fernandez N , Luis Garcia‐Villalon A , Sanchez Turrion V , Cuervas‐Mons V , Dieguez G . Apelin effects in human splanchnic arteries. Role of nitric oxide and prostanoids. Regul Pept 144: 50‐55, 2007.
 303. Salgado‐Somoza A , Teijeira‐Fernandez E , Fernandez AL , Gonzalez‐Juanatey JR , Eiras S . Proteomic analysis of epicardial and subcutaneous adipose tissue reveals differences in proteins involved in oxidative stress. J Physiol Heart Circ Physiol 299: H202‐H209, 2010.
 304. Samal B , Sun Y , Stearns G , Xie C , Suggs S , McNiece I . Cloning and characterization of the cDNA encoding a novel human pre‐B‐cell colony‐enhancing factor. Mol Cell Biol 14: 1431‐1437, 1994.
 305. Sandoo A , Panoulas VF , Toms TE , Smith JP , Stavropoulos‐Kalinoglou A , Metsios GS , Gasparyan AY , Carroll D , Veldhuijzen van Zanten JJ , Kitas GD . Anti‐TNFalpha therapy may lead to blood pressure reductions through improved endothelium‐dependent microvascular function in patients with rheumatoid arthritis. J Hum Hypertens 25: 699‐702, 2011.
 306. Savage DB , Sewter CP , Klenk ES , Segal DG , Vidal‐Puig A , Considine RV , O'Rahilly S . Resistin/Fizz3 expression in relation to obesity and peroxisome proliferator‐activated receptor‐gamma action in humans. Diabetes 50: 2199‐2202, 2001.
 307. Scatena M , Liaw L , Giachelli CM . Osteopontin: a multifunctional molecule regulating chronic inflammation and vascular disease. Arterioscler Thromb Vasc Biol 27: 2302‐2309, 2007.
 308. Schleifenbaum J , Kohn C , Voblova N , Dubrovska G , Zavarirskaya O , Gloe T , Crean CS , Luft FC , Huang Y , Schubert R , Gollasch M . Systemic peripheral artery relaxation by KCNQ channel openers and hydrogen sulfide. J Hypertens 28: 1875‐1882, 2010.
 309. Schlich R , Lamers D , Eckel J , Sell H . Adipokines enhance oleic acid‐induced proliferation of vascular smooth muscle cells by inducing CD36 expression. Arch Physiol Biochem 121: 81‐87, 2015.
 310. Schlich R , Willems M , Greulich S , Ruppe F , Knoefel WT , Ouwens DM , Maxhera B , Lichtenberg A , Eckel J , Sell H . VEGF in the crosstalk between human adipocytes and smooth muscle cells: Depot‐specific release from visceral and perivascular adipose tissue. Mediators Inflamm 2013: 982458, 2013.
 311. Schmid PM , Resch M , Schach C , Birner C , Riegger GA , Luchner A , Endemann DH . Antidiabetic treatment restores adiponectin serum levels and APPL1 expression, but does not improve adiponectin‐induced vasodilation and endothelial dysfunction in Zucker diabetic fatty rats. Cardiovasc Diabetol 12: 46, 2013.
 312. Schrader LI , Kinzenbaw DA , Johnson AW , Faraci FM , Didion SP . IL‐6 deficiency protects against angiotensin II induced endothelial dysfunction and hypertrophy. Arterioscler Thromb Vasc Biol 27: 2576‐2581, 2007.
 313. Schroeter MR , Eschholz N , Herzberg S , Jerchel I , Leifheit‐Nestler M , Czepluch FS , Chalikias G , Konstantinides S , Schafer K . Leptin‐dependent and leptin‐independent paracrine effects of perivascular adipose tissue on neointima formation. Arterioscler Thromb Vasc Biol 33: 980‐987, 2013.
 314. Seifalian AM , Filippatos TD , Joshi J , Mikhailidis DP . Obesity and arterial compliance alterations. Curr Vasc Pharmacol 8: 155‐168, 2010.
 315. Selcuk A , Bulucu F , Kalafat F , Cakar M , Demirbas S , Karaman M , Ay SA , Saglam K , Balta S , Demirkol S , Arslan E . Skinfold thickness as a predictor of arterial stiffness: obesity and fatness linked to higher stiffness measurements in hypertensive patients. Clin Exp Hypertens 35: 459‐464, 2013.
 316. Sharma G , Kulkarni R , Shah SK , King WW , Longchamp A , Tao M , Ding K , Ozaki CK . Local perivascular adiponectin associates with lower extremity vascular operative wound complications. Surgery 160: 204‐210, 2016.
 317. Sharma G , Tao M , Ding K , Yu D , King W , Deyneko G , Wang X , Longchamp A , Schoen FJ , Ozaki CK , Semel ME . Perivascular adipose adiponectin correlates with symptom status of patients undergoing carotid endarterectomy. Stroke 46: 1696‐1699, 2015.
 318. Shetty GK , Economides PA , Horton ES , Mantzoros CS , Veves A . Circulating adiponectin and resistin levels in relation to metabolic factors, inflammatory markers, and vascular reactivity in diabetic patients and subjects at risk for diabetes. Diabetes Care 27: 2450‐2457, 2004.
 319. Shi Y , So KF , Man RY , Vanhoutte PM . Oxygen‐derived free radicals mediate endothelium‐dependent contractions in femoral arteries of rats with streptozotocin‐induced diabetes. Br J Pharmacol 152: 1033‐1041, 2007.
 320. Shibata M , Parfenova H , Zuckerman SL , Leffler CW . Tumor necrosis factor‐alpha induces pial arteriolar dilation in newborn pigs. Brain Res Bull 39: 241‐247, 1996.
 321. Shibata M , Parfenova H , Zuckerman SL , Seyer JM , Krueger JM , Leffler CW . Interleukin‐1 beta peptides induce cerebral pial arteriolar dilation in anesthetized newborn pigs. Am J Physiol 270: R1044‐R1050, 1996.
 322. Shimabukuro M , Higa N , Asahi T , Oshiro Y , Takasu N , Tagawa T , Ueda S , Shimomura I , Funahashi T , Matsuzawa Y . Hypoadiponectinemia is closely linked to endothelial dysfunction in man. J Clin Endocrinol Metab 88: 3236‐3240, 2003.
 323. Siegel‐Axel DI , Haring HU. Perivascular adipose tissue: An unique fat compartment relevant for the cardiometabolic syndrome. Rev Endocr Metab Disord 17: 51‐60, 2016.
 324. Siegel‐Axel DI , Viehban R , Betz EL , Karsch KR . Progress in the research of atherosclerosis and restenosis using an in vitro method: Transfilter cocultures with human vascular cells. ALTEX 16: 117, 1999.
 325. Simonds SE , Pryor JT , Ravussin E , Greenway FL , Dileone R , Allen AM , Bassi J , Elmquist JK , Keogh JM , Henning E , Myers MG, Jr. , Licinio J , Brown RD , Enriori PJ , O'Rahilly S , Sternson SM , Grove KL , Spanswick DC , Farooqi IS , Cowley MA . Leptin mediates the increase in blood pressure associated with obesity. Cell 159: 1404‐1416, 2014.
 326. Sizemore N , Leung S , Stark GR . Activation of phosphatidylinositol 3‐kinase in response to interleukin‐1 leads to phosphorylation and activation of the NF‐kappaB p65/RelA subunit. Mol Cell Biol 19: 4798‐4805, 1999.
 327. Soltis EE , Cassis LA. Influence of perivascular adipose tissue on rat aortic smooth muscle responsiveness. Clin Exp Hypertens A 13: 277‐296, 1991.
 328. Somoza B , Guzman R , Cano V , Merino B , Ramos P , Diez‐Fernandez C , Fernandez‐Alfonso MS , Ruiz‐Gayo M . Induction of cardiac uncoupling protein‐2 expression and adenosine 5′‐monophosphate‐activated protein kinase phosphorylation during early states of diet‐induced obesity in mice. Endocrinology 148: 924‐931, 2007.
 329. Sriramula S , Haque M , Majid DS , Francis J . Involvement of tumor necrosis factor‐alpha in angiotensin II‐mediated effects on salt appetite, hypertension, and cardiac hypertrophy. Hypertension 51: 1345‐1351, 2008.
 330. Sun X , Hou N , Han F , Guo Y , Hui Z , Du G , Zhang Y . Effect of high free fatty acids on the anti‐contractile response of perivascular adipose tissue in rat aorta. J Mol Cell Cardiol 63: 169‐174, 2013.
 331. Szasz T , Bomfim GF , Webb RC . The influence of perivascular adipose tissue on vascular homeostasis. Vasc Health Risk Manag 9: 105‐116, 2013.
 332. Takaoka M , Nagata D , Kihara S , Shimomura I , Kimura Y , Tabata Y , Saito Y , Nagai R , Sata M . Periadventitial adipose tissue plays a critical role in vascular remodeling. Circ Res 105: 906‐911, 2009.
 333. Takaoka M , Suzuki H , Shioda S , Sekikawa K , Saito Y , Nagai R , Sata M . Endovascular injury induces rapid phenotypic changes in perivascular adipose tissue. Arterioscler Thromb Vasc Biol 30: 1576‐1582, 2010.
 334. Takizawa S , Ozaki H , Karaki H . Interleukin‐1beta‐induced, nitric oxide‐dependent and ‐independent inhibition of vascular smooth muscle contraction. Eur J Pharmacol 330: 143‐150, 1997.
 335. Takizawa S , Ozaki H , Karaki H . Possible involvement of K+ channel opening to the interleukin‐1 beta‐induced inhibition of vascular smooth muscle contraction. J Vet Med Sci 61: 357‐360, 1999.
 336. Tan YL , Zheng XL , Tang CK . The protective functions of omentin in cardiovascular diseases. Clin Chim Acta 448: 98‐106, 2015.
 337. Tano JY , Gollasch M. Calcium‐activated potassium channels in ischemia reperfusion: A brief update. Front Physiol 5: 381, 2014.
 338. Tatemoto K. Search for an endogenous ligand of the orphan G protein‐coupled receptor—discovery of apelin, a novel biologically active peptide. Nihon Rinsho 58: 737‐746, 2000.
 339. Tatemoto K , Hosoya M , Habata Y , Fujii R , Kakegawa T , Zou MX , Kawamata Y , Fukusumi S , Hinuma S , Kitada C , Kurokawa T , Onda H , Fujino M . Isolation and characterization of a novel endogenous peptide ligand for the human APJ receptor. Biochem Biophys Res Commun 251: 471‐476, 1998.
 340. Tatemoto K , Takayama K , Zou MX , Kumaki I , Zhang W , Kumano K , Fujimiya M . The novel peptide apelin lowers blood pressure via a nitric oxide‐dependent mechanism. Regul Pept 99: 87‐92, 2001.
 341. Tchkonia T , Thomou T , Zhu Y , Karagiannides I , Pothoulakis C , Jensen MD , Kirkland JL . Mechanisms and metabolic implications of regional differences among fat depots. Cell Metab 17: 644‐656, 2013.
 342. Testai L , Marino A , Piano I , Brancaleone V , Tomita K , Di Cesare Mannelli L , Martelli A , Citi V , Breschi MC , Levi R , Gargini C , Bucci M , Cirino G , Ghelardini C , Calderone V . The novel H2S‐donor 4‐carboxyphenyl isothiocyanate promotes cardioprotective effects against ischemia/reperfusion injury through activation of mitoKATP channels and reduction of oxidative stress. Pharmacol Res 113: 290‐299, 2016.
 343. Thanassoulis G , Massaro JM , O'Donnell CJ , Hoffmann U , Levy D , Ellinor PT , Wang TJ , Schnabel RB , Vasan RS , Fox CS , Benjamin EJ . Pericardial fat is associated with prevalent atrial fibrillation: The Framingham Heart Study. Circ Arrhythm Electrophysiol 3: 345‐350, 2010.
 344. Thijs AM , van Herpen CM , Sweep FC , Geurts‐Moespot A , Smits P , van der Graaf WT , Rongen GA . Role of endogenous vascular endothelial growth factor in endothelium‐dependent vasodilation in humans. Hypertension 61: 1060‐1065, 2013.
 345. Thundyil J , Pavlovski D , Sobey CG , Arumugam TV . Adiponectin receptor signalling in the brain. Br J Pharmacol 165: 313‐327, 2012.
 346. Tian Z , Miyata K , Tazume H , Sakaguchi H , Kadomatsu T , Horio E , Takahashi O , Komohara Y , Araki K , Hirata Y , Tabata M , Takanashi S , Takeya M , Hao H , Shimabukuro M , Sata M , Kawasuji M , Oike Y . Perivascular adipose tissue‐secreted angiopoietin‐like protein 2 (Angptl2) accelerates neointimal hyperplasia after endovascular injury. J Mol Cell Cardiol 57: 1‐12, 2013.
 347. Timmons JA , Baar K , Davidsen PK , Atherton PJ . Is irisin a human exercise gene? Nature 488: E9‐E10; discussion E10‐11, 2012.
 348. Tracey KJ , Cerami A. Tumor necrosis factor: A pleiotropic cytokine and therapeutic target. Annu Rev Med 45: 491‐503, 1994.
 349. Tsvetkov D , Shymanets A , Huang Y , Bucher K , Piekorz R , Hirsch E , Beer‐Hammer S , Harteneck C , Gollasch M , Nurnberg B . Better understanding of phosphoinositide 3‐kinase (PI3K) pathways in vasculature: Towards precision therapy targeting angiogenesis and tumor blood supply. Biochemistry Biokhimiia 81: 691‐699, 2016.
 350. Tsvetkov D , Tano JY , Kassmann M , Wang N , Schubert R , Gollasch M . The role of DPO‐1 and XE991‐sensitive potassium channels in perivascular adipose tissue‐mediated regulation of vascular tone. Front Physiol 7: 335, 2016.
 351. Turu MM , Slevin M , Matou S , West D , Rodriguez C , Luque A , Grau‐Olivares M , Badimon L , Martinez‐Gonzalez J , Krupinski J . C‐reactive protein exerts angiogenic effects on vascular endothelial cells and modulates associated signalling pathways and gene expression. BMC Cell Biol 9: 47, 2008.
 352. Tuttolomondo A , Pecoraro R , Butta C , Di Raimondo D , Ferrante A , Della Corte V , Ciccia F , Bellia C , Giardina A , Raffa A , Ciaccio M , Pinto A . Arterial stiffness indexes and serum cytokine levels in seronegative spondyloarthritis: Relationships between stiffness markers and metabolic and immunoinflammatory variables. Scand J Rheumatol 44: 474‐479, 2015.
 353. Uchida Y , Uchida Y , Shimoyama E , Hiruta N , Kishimoto T , Watanabe S . Pericoronary adipose tissue as storage and supply site for oxidized low‐density lipoprotein in human coronary plaques. PloS One 11: e0150862, 2016.
 354. Uemura Y , Shibata R , Kanemura N , Ohashi K , Kambara T , Hiramatsu‐Ito M , Enomoto T , Yuasa D , Joki Y , Matsuo K , Ito M , Hayakawa S , Ogawa H , Murohara T , Ouchi N . Adipose‐derived protein omentin prevents neointimal formation after arterial injury. FASEB J 29: 141‐151, 2015.
 355. Uhlen M , Fagerberg L , Hallstrom BM , Lindskog C , Oksvold P , Mardinoglu A , Sivertsson A , Kampf C , Sjostedt E , Asplund A , Olsson I , Edlund K , Lundberg E , Navani S , Szigyarto CA , Odeberg J , Djureinovic D , Takanen JO , Hober S , Alm T , Edqvist PH , Berling H , Tegel H , Mulder J , Rockberg J , Nilsson P , Schwenk JM , Hamsten M , von Feilitzen K , Forsberg M , Persson L , Johansson F , Zwahlen M , von Heijne G , Nielsen J , Ponten F . Proteomics. Tissue‐based map of the human proteome. Science 347: 1260419, 2015.
 356. Ulu A , Stephen Lee KS , Miyabe C , Yang J , Hammock BG , Dong H , Hammock BD . An omega‐3 epoxide of docosahexaenoic acid lowers blood pressure in angiotensin‐II‐dependent hypertension. J Cardiovasc Pharmacol 64: 87‐99, 2014.
 357. Vallejo S , Romacho T , Angulo J , Villalobos LA , Cercas E , Leivas A , Bermejo E , Carraro R , Sanchez‐Ferrer CF , Peiro C . Visfatin impairs endothelium‐dependent relaxation in rat and human mesenteric microvessels through nicotinamide phosphoribosyltransferase activity. PLoS One 6: e27299, 2011.
 358. van Leeuwen MA , Westra J , Limburg PC , van Riel PL , van Rijswijk MH . Interleukin‐6 in relation to other proinflammatory cytokines, chemotactic activity and neutrophil activation in rheumatoid synovial fluid. Ann Rheum Dis 54: 33‐38, 1995.
 359. Vecchione C , Colella S , Fratta L , Gentile MT , Selvetella G , Frati G , Trimarco B , Lembo G . Impaired insulin‐like growth factor I vasorelaxant effects in hypertension. Hypertension 37: 1480‐1485, 2001.
 360. Vecchione C , Maffei A , Colella S , Aretini A , Poulet R , Frati G , Gentile MT , Fratta L , Trimarco V , Trimarco B , Lembo G . Leptin effect on endothelial nitric oxide is mediated through Akt‐endothelial nitric oxide synthase phosphorylation pathway. Diabetes 51: 168‐173, 2002.
 361. Vecchione C , Patrucco E , Marino G , Barberis L , Poulet R , Aretini A , Maffei A , Gentile MT , Storto M , Azzolino O , Brancaccio M , Colussi GL , Bettarini U , Altruda F , Silengo L , Tarone G , Wymann MP , Hirsch E , Lembo G . Protection from angiotensin II‐mediated vasculotoxic and hypertensive response in mice lacking PI3Kgamma. J Exp Med 201: 1217‐1228, 2005.
 362. Verhagen SN , Buijsrogge MP , Vink A , van Herwerden LA , van der Graaf Y , Visseren FL . Secretion of adipocytokines by perivascular adipose tissue near stenotic and non‐stenotic coronary artery segments in patients undergoing CABG. Atherosclerosis 233: 242‐247, 2014.
 363. Verhagen SN , Visseren FL. Perivascular adipose tissue as a cause of atherosclerosis. Atherosclerosis 214: 3‐10, 2011.
 364. Verlohren S , Dubrovska G , Tsang SY , Essin K , Luft FC , Huang Y , Gollasch M . Visceral periadventitial adipose tissue regulates arterial tone of mesenteric arteries. Hypertension 44: 271‐276, 2004.
 365. Verma S , Li SH , Wang CH , Fedak PW , Li RK , Weisel RD , Mickle DA . Resistin promotes endothelial cell activation: Further evidence of adipokine‐endothelial interaction. Circulation 108: 736‐740, 2003.
 366. Vicaut E , Rasetti C , Baudry N . Effects of tumor necrosis factor and interleukin‐1 on the constriction induced by angiotensin II in rat aorta. J Appl Physiol 80: 1891‐1897, 1996.
 367. Villacorta L , Chang L. The role of perivascular adipose tissue in vasoconstriction, arterial stiffness, and aneurysm. Horm Mol Biol Clin Investig 21: 137‐147, 2015.
 368. Virdis A , Duranti E , Rossi C , Dell'Agnello U , Santini E , Anselmino M , Chiarugi M , Taddei S , Solini A . Tumour necrosis factor‐alpha participates on the endothelin‐1/nitric oxide imbalance in small arteries from obese patients: Role of perivascular adipose tissue. Eur Heart J 36: 784‐794, 2015.
 369. Wagner R , Machann J , Lehmann R , Rittig K , Schick F , Lenhart J , Artunc F , Linder K , Claussen CD , Schleicher E , Fritsche A , Haring HU , Weyrich P . Exercise‐induced albuminuria is associated with perivascular renal sinus fat in individuals at increased risk of type 2 diabetes. Diabetologia 55: 2054‐2058, 2012.
 370. Wakana N , Irie D , Kikai M , Terada K , Yamamoto K , Kawahito H , Kato T , Ogata T , Ueyama T , Matoba S , Yamada H . Maternal high‐fat diet exaggerates atherosclerosis in adult offspring by augmenting periaortic adipose tissue‐specific proinflammatory response. Arterioscler Thromb Vasc Biol 35: 558‐569, 2015.
 371. Wang B , Jenkins JR , Trayhurn P . Expression and secretion of inflammation‐related adipokines by human adipocytes differentiated in culture: Integrated response to TNF‐alpha. Am J Physiol Endocrinol Metab 288: E731‐E740, 2005.
 372. Wang D , Wang C , Wu X , Zheng W , Sandberg K , Ji H , Welch WJ , Wilcox CS . Endothelial dysfunction and enhanced contractility in microvessels from ovariectomized rats: roles of oxidative stress and perivascular adipose tissue. Hypertension 63: 1063‐1069, 2014.
 373. Wang H , Luo W , Wang J , Guo C , Wang X , Wolffe SL , Bodary PF , Eitzman DT . Obesity‐induced endothelial dysfunction is prevented by deficiency of P‐selectin glycoprotein ligand‐1. Diabetes 61: 3219‐3227, 2012.
 374. Wang P , Xu TY , Guan YF , Su DF , Fan GR , Miao CY . Perivascular adipose tissue‐derived visfatin is a vascular smooth muscle cell growth factor: Role of nicotinamide mononucleotide. Cardiovasc Res 81: 370‐380, 2009.
 375. Wang T , Zhang X , Bheda P , Revollo JR , Imai S , Wolberger C . Structure of Nampt/PBEF/visfatin, a mammalian NAD+ biosynthetic enzyme. Nat Struct Mol Biol 13: 661‐662, 2006.
 376. Wang X , Lin Y , Luo N , Chen Z , Gu M , Wang J , Chen Y . Short‐term intensive atorvastatin therapy improves endothelial function partly via attenuating perivascular adipose tissue inflammation through 5‐lipoxygenase pathway in hyperlipidemic rabbits. Chin Med J (Engl) 127: 2953‐2959, 2014.
 377. Wang Y , Liu H , McKenzie G , Witting PK , Stasch JP , Hahn M , Changsirivathanathamrong D , Wu BJ , Ball HJ , Thomas SR , Kapoor V , Celermajer DS , Mellor AL , Keaney JF, Jr. , Hunt NH , Stocker R . Kynurenine is an endothelium‐derived relaxing factor produced during inflammation. Nat Med 16: 279‐285, 2010.
 378. Watts SW , Shaw S , Burnett R , Dorrance AM . Indoleamine 2,3‐diooxygenase in periaortic fat: Mechanisms of inhibition of contraction. J Physiol Heart Circ Physiol 301: H1236‐H1247, 2011.
 379. Wedmann R , Onderka C , Wei S , Szijarto IA , Miljkovic JL , Mitrovic A , Lange M , Savitsky S , Yadav PK , Torregrossa R , Harrer EG , Harrer T , Ishii I , Gollasch M , Wood ME , Galardon E , Xian M , Whiteman M , Banerjee R , Filipovic MR . Improved tag‐switch method reveals that thioredoxin acts as depersulfidase and controls the intracellular levels of protein persulfidation. Chem Sci 7: 3414‐3426, 2016.
 380. Werner H , Weinstein D , Bentov I . Similarities and differences between insulin and IGF‐I: Structures, receptors, and signalling pathways. Arch Physiol Biochem 114: 17‐22, 2008.
 381. Wimalasundera R , Fexby S , Regan L , Thom SA , Hughes AD . Effect of tumour necrosis factor‐alpha and interleukin 1beta on endothelium‐dependent relaxation in rat mesenteric resistance arteries in vitro. Br J Pharmacol 138: 1285‐1294, 2003.
 382. Winther AK , Dalsgaard T , Hedegaard ER , Simonsen U . Involvement of hydrogen sulfide in perivascular and hypoxia‐induced inhibition of endothelin contraction in porcine retinal arterioles. Nitric Oxide 50: 1‐9, 2015.
 383. Withers SB , Bussey CE , Saxton SN , Melrose HM , Watkins AE , Heagerty AM . Mechanisms of adiponectin‐associated perivascular function in vascular disease. Arterioscler Thromb Vasc Biol 34: 1637‐1642, 2014.
 384. Withers SB , Simpson L , Fattah S , Werner ME , Heagerty AM . cGMP‐dependent protein kinase (PKG) mediates the anticontractile capacity of perivascular adipose tissue. Cardiovasc Res 101: 130‐137, 2014.
 385. Yamawaki H , Hara N , Okada M , Hara Y . Visfatin causes endothelium‐dependent relaxation in isolated blood vessels. Biochem Biophys Res Commun 383: 503‐508, 2009.
 386. Yamawaki H , Kuramoto J , Kameshima S , Usui T , Okada M , Hara Y . Omentin, a novel adipocytokine inhibits TNF‐induced vascular inflammation in human endothelial cells. Biochem Biophys Res Commun 408: 339‐343, 2011.
 387. Yamawaki H , Tsubaki N , Mukohda M , Okada M , Hara Y . Omentin, a novel adipokine, induces vasodilation in rat isolated blood vessels. Biochem Biophys Res Commun 393: 668‐672, 2010.
 388. Yang AL , Chao JI , Lee SD . Altered insulin‐mediated and insulin‐like growth factor‐1‐mediated vasorelaxation in aortas of obese Zucker rats. Int J Obes 31: 72‐77, 2007.
 389. Yang AL , Lo CW , Lee JT , Su CT . Enhancement of vasorelaxation in hypertension following high‐intensity exercise. Chin J Physiol 54: 87‐95, 2011.
 390. Yang AL , Su CT , Lin KL , Lee SD . Enhancement of vascular function mediated by insulin and insulin‐like growth factor‐1 following single exercise session. Chin J Physiol 51: 71‐77, 2008.
 391. Yang RZ , Lee MJ , Hu H , Pray J , Wu HB , Hansen BC , Shuldiner AR , Fried SK , McLenithan JC , Gong DW . Identification of omentin as a novel depot‐specific adipokine in human adipose tissue: Possible role in modulating insulin action. Am J Physiol Endocrinol Metab 290: E1253‐E1261, 2006.
 392. Yang WS , Han NJ , Kim JJ , Lee MJ , Park SK . TNF‐alpha activates high‐mobility group box 1—toll‐like receptor 4 signaling pathway in human aortic endothelial cells. Cell Physiol Biochem 38: 2139‐2151, 2016.
 393. Ye S , Mozayeni P , Gamburd M , Zhong H , Campese VM . Interleukin‐1beta and neurogenic control of blood pressure in normal rats and rats with chronic renal failure. J Physiol Heart Circ Physiol 279: H2786‐H2796, 2000.
 394. Yoo JK , Hwang MH , Luttrell MJ , Kim HK , Meade TH , English M , Segal MS , Christou DD . Higher levels of adiponectin in vascular endothelial cells are associated with greater brachial artery flow‐mediated dilation in older adults. Exp Gerontol 63: 1‐7, 2015.
 395. Yoshida S , Takeuchi T , Kotani T , Yamamoto N , Hata K , Nagai K , Shoda T , Takai S , Makino S , Hanafusa T . Infliximab, a TNF‐alpha inhibitor, reduces 24‐h ambulatory blood pressure in rheumatoid arthritis patients. J Hum Hypertens 28: 165‐169, 2014.
 396. Yudkin JS , Eringa E , Stehouwer CD . “Vasocrine” signalling from perivascular fat: A mechanism linking insulin resistance to vascular disease. Lancet 365: 1817‐1820, 2005.
 397. Zaborska KE , Wareing M , Edwards G , Austin C . Loss of anti‐contractile effect of perivascular adipose tissue in offspring of obese rats. Int J Obes 40: 1205-1214, 2016.
 398. Zavaritskaya O , Zhuravleva N , Schleifenbaum J , Gloe T , Devermann L , Kluge R , Mladenov M , Frey M , Gagov H , Fesus G , Gollasch M , Schubert R . Role of KCNQ channels in skeletal muscle arteries and periadventitial vascular dysfunction. Hypertension 61: 151‐159, 2013.
 399. Zeidan A , Paylor B , Steinhoff KJ , Javadov S , Rajapurohitam V , Chakrabarti S , Karmazyn M . Actin cytoskeleton dynamics promotes leptin‐induced vascular smooth muscle hypertrophy via RhoA/ROCK‐ and phosphatidylinositol 3‐kinase/protein kinase B‐dependent pathways. J Pharmacol Exp Ther 322: 1110‐1116, 2007.
 400. Zeng G , Nystrom FH , Ravichandran LV , Cong LN , Kirby M , Mostowski H , Quon MJ . Roles for insulin receptor, PI3‐kinase, and Akt in insulin‐signaling pathways related to production of nitric oxide in human vascular endothelial cells. Circulation 101: 1539‐1545, 2000.
 401. Zeng ZH , Zhang ZH , Luo BH , He WK , Liang LY , He CC , Su CJ . The functional changes of the perivascular adipose tissue in spontaneously hypertensive rats and the effects of atorvastatin therapy. Clin Exp Hypertens 31: 355‐363, 2009.
 402. Zhang H , Huang Y , Bu D , Chen S , Tang C , Wang G , Du J , Jin H . Endogenous sulfur dioxide is a novel adipocyte‐derived inflammatory inhibitor. Sci Rep 6: 27026, 2016.
 403. Zhang W , Chang L , Zhang C , Zhang R , Li Z , Chai B , Li J , Chen E , Mulholland M . Central and peripheral irisin differentially regulate blood pressure. Cardiovasc Drugs Ther 29: 121‐127, 2015.
 404. Zhong JC , Huang Y , Yung LM , Lau CW , Leung FP , Wong WT , Lin SG , Yu XY . The novel peptide apelin regulates intrarenal artery tone in diabetic mice. Regul Pept 144: 109‐114, 2007.
 405. Zhong JC , Yu XY , Huang Y , Yung LM , Lau CW , Lin SG . Apelin modulates aortic vascular tone via endothelial nitric oxide synthase phosphorylation pathway in diabetic mice. Cardiovasc Res 74: 388‐395, 2007.
 406. Zhou JY , Chan L , Zhou SW . Omentin: Linking metabolic syndrome and cardiovascular disease. Curr Vasc Pharmacol 12: 136‐143, 2014.
 407. Zuk PA , Zhu M , Ashjian P , De Ugarte DA , Huang JI , Mizuno H , Alfonso ZC , Fraser JK , Benhaim P , Hedrick MH . Human adipose tissue is a source of multipotent stem cells. Mol Biol Cell 13: 4279‐4295, 2002.

 

Teaching Material

M. S. Fernández-Alfonso, B. Somoza, D. Tsvetkov, A. Kuczmanski, M. Dashwood, M. Gil-Ortega. Role of Perivascular Adipose Tissue in Health and Disease. Compr Physiol. 8: 2018, 23-59.

Didactic Synopsis

Major Teaching Points:

  • Understanding the features and roles of different PVATs to master their influence in vascular homeostasis in health and disease.
  • Vasoactive factors released by PVAT:
    • Relaxing factors: leptin, adiponectin, visfatin, irisin, omentin, apelin, H2O2, H2S, FFAs, Ang 1-7, IL-1, and IGF-1.
    • Contractile factors: sympathetic neurotransmitters, Ang II, resistin, H2S, IL-1, IL-6, TNF-a.
  • Physiologic roles of PVAT:
    • Regulation of vascular function
    • Protection atherosclerosis, macrophage infiltration, and hypoxia
    • Protection against wave torsion and hypothermia
    • Regulation of muscle perfusion and insulin sensitivity
    • Beneficial effects on CABG surgery
    • Anti-inflammatory effects
  • Pathologic roles of dysfunctional PVAT:
    • In obesity:
      • Loss of anticontractile effects
      • Contribution to vascular alterations, insulin resistance, inflammation, and hypoxia
    • In hypertension:
      • Reduced anticontractile effect
    • In atherosclerosis:
      • Contribution to the development and destabilization of atherosclerotic plaques
    • In menopause:
      • Increase of cardiovascular risk
  • Understanding the causal link between PVAT and most of the aforementioned effects is based on association/outcome data obtained in animal models or patients. Further supporting research is necessary to demonstrate a cause-effect relationship.

 

 


Contact Editor

Submit a note to the editor about this article by filling in the form below.

* Required Field

Article Title: Role of Perivascular Adipose Tissue in Health and Disease
 

How to Cite

Maria S. Fernández‐Alfonso, Beatriz Somoza, Dmitry Tsvetkov, Artur Kuczmanski, Mick Dashwood, Marta Gil‐Ortega. Role of Perivascular Adipose Tissue in Health and Disease. Compr Physiol 2017, 8: 23-59. doi: 10.1002/cphy.c170004