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Role of Perivascular Adipose Tissue in Health and Disease

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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.

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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 (). (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 (). (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 ().
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 () 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 (O2), and hydrogen peroxide (H2O2). O2 is transformed into H2O2 by the superoxide dismutase (SOD). High levels of O2 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 (O2) 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 (). (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 (). (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 ().


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 () 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 (O2), and hydrogen peroxide (H2O2). O2 is transformed into H2O2 by the superoxide dismutase (SOD). High levels of O2 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 (O2) 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).
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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.

 

 


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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