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Impact of Metabolic Diseases on Cerebral Circulation: Structural and Functional Consequences

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ABSTRACT

Metabolic diseases including obesity, insulin resistance, and diabetes have profound effects on cerebral circulation. These diseases not only affect the architecture of cerebral blood arteries causing adverse remodeling, pathological neovascularization, and vasoregression but also alter the physiology of blood vessels resulting in compromised myogenic reactivity, neurovascular uncoupling, and endothelial dysfunction. Coupled with the disruption of blood brain barrier (BBB) integrity, changes in blood flow and microbleeds into the brain rapidly occur. This overview is organized into sections describing cerebrovascular architecture, physiology, and BBB in these diseases. In each section, we review these properties starting with larger arteries moving into smaller vessels. Where information is available, we review in the order of obesity, insulin resistance, and diabetes. We also tried to include information on biological variables such as the sex of the animal models noted since most of the information summarized was obtained using male animals. © 2018 American Physiological Society. Compr Physiol 8:773‐799, 2018.

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Figure 1. Figure 1. Schematic illustration depicting the impact of metabolic diseases on structural and functional properties of cerebral circulation. Obesity, insulin resistance, and diabetes alter physiology and structure of the cerebrovasculature leading to dysregulation of cerebral blood flow (CBF) as well as increase the risk and severity of central nervous systems complications including stroke, cognitive impairment, and neurodegeneration.
Figure 2. Figure 2. (A) Illustration of the carotid and vertebrobasilar arteries, main arterial supplies of the brain. (B) The arteries at the base of the brain. Internal carotid arteries (ICA) and basilar artery (BA) join to form the Circle of Willis which gives rise to cerebral arteries: anterior (ACA), middle (MCA), and posterior (PCA) cerebral arteries. Used with permission from (189).
Figure 3. Figure 3. Representative illustration of the angioarchitecture of the cortex demonstrating the top level of surface arteries and arterioles feeding into the subsurface capillary network via penetrating arterioles. Modified and used with permission from (94).
Figure 4. Figure 4. Illustration of the mechanisms of myogenic tone development. Pressure increase in the arterial wall is sensed by mechanoreceptors leading to an increase in intracellular Ca2+. Subsequently, myosin light chain kinase (MLCK) is activated leading to myosin phosphorylation and actin polymerization culminating in vasoconstriction. Rapid dephosphorylation of myosin heavy chain by myosin light chain phosphatase (MLCP) promotes relaxation. Activation of Rho‐associated kinase (ROCK) inhibits MLCP and contributes to sustained contraction. Modified and used with permission from (249).
Figure 5. Figure 5. (A) MCA isolated from (10–12 week) diabetic rats experienced increased myogenic tone compared to control. (*p < 0.05 vs. control, n = 6‐8). Used with permission from (139). (B) Twenty‐two‐week‐old diabetic rats experienced impaired myogenic reactivity compared to age‐matched control rats. Treatment with azilsartan restored myogenic tone of diabetic rats. (*p < 0.05 vs. Wis, #p < 0.05 vs. vehicle, n = 6‐8/group). Modified with permission from (2).
Figure 6. Figure 6. The working model for vasculoneuronal coupling. Increased luminal pressure causes constriction of parenchymal arteriole leading to increased Ca2+ in astrocytes via the activation of TRPV4 channels. This signal contributes to maintenance of vascular tone as well as inhibition of pyramidal neuron firing activity. It is postulated that pressure‐evoked parenchymal arteriole constriction and increased astrocytic Ca2+ can further modulate pyramidal neuron resting activity via somatostatin interneurons (dotted lines). Modified with permission from (141).
Figure 7. Figure 7. (A) Representative image of CBF in both diabetic and control rats generated by magnetic resonance imaging. Scale bar for color‐coding is shown below. (B) CBF was reduced in the parietal cortex and striatum of diabetic rats compared to control. (C) Time course of cortical laser‐Doppler flow in both control and diabetic rats during whisker stimulation in anesthetized animals. (D) Bar graph showing the increase in CBF during whisker stimulation, which was significantly reduced in diabetic versus control rat. (*p < 0.05 vs. cortex; p < 0.001 vs. control, n = 4‐12). Modified with permission from (139).
Figure 8. Figure 8. CBF is different in early and late stage diabetic mice. Representative images of cortical perfusion obtained with laser speckle (A) and whole brain perfusion obtained with MRI FAIR‐RARE (B) imaging are shown on top and collective data are summarized in bar graphs below. Laser speckle imaging reveals that at 6 weeks cortical perfusion in brain areas supplied by the MCA is decreased in diabetic animals. At 14 weeks after the onset of diabetes, diabetic mice exhibit an increase in whole‐brain perfusion compared to control mice. n = 4/group, *p < 0.05 versus control. Used with permission from (111).
Figure 9. Figure 9. Illustration of the angiogenesis and arteriogenesis cascade. Used with permission from (83).
Figure 10. Figure 10. Illustration of the retinal acellular capillary, a model of vasoregression in metabolic diseases. Acellular capillaries in the retinal vasculature are indicated by yellow arrows. Diabetes increases retinal acellular capillaries compared to control retina.
Figure 11. Figure 11. Glycemic control prevents deranged vascularization in diabetes. (A) Representative images of surface pial arteries in control (C), diabetes (D), and diabetes + metformin (D + M) groups. Number of collaterals quantified from these images (shown on the bar graph on the right) is significantly higher in diabetes and it is prevented by glycemic control with metformin. Mean ± SEM, n = 7 to 14, *p < 0.0001 versus C, **p < 0.001 versus D. Modified with permission from (78). Representative images showing (B) vascular branching on pial arteries and surface cortical vessels taken under 10 × and (C) inner vessel walls outlined using the Fiji software. Diabetic GK rats exhibit profound increase in branch density and diameter of pial arteries. While there was no significant change in branching of pial arteries with glycemic control, lumen diameter, and tortuosity was reduced. *p < 0.01 versus control, **p < 0.001 versus control or treatment. Mean ± SEM, n = 6 to 8. Modified with permission from (201).
Figure 12. Figure 12. Inhibition of VEGF signaling repairs pathological cerebral neovascularization in diabetes. Diabetic rats with established pathological neovascularization were assigned for treatment with vehicle or the VEGFR‐2 inhibitor, SLKB1002 (10 mg/kg/day) for 2 weeks. SLKB1002 significantly decreased all neovascularization indices (n = 5‐6, *, Ψp < 0.05). Used with permission from (3).
Figure 13. Figure 13. Illustration of blood supply to the hippocampus. The main supply to the hippocampus usually arises from the posterior circulation via single or multiple middle and posterior hippocampal arteries. ACA, anterior cerebral artery; ICA, internal carotid artery; MCA, middle cerebral artery; PcomA, posterior communicating artery; and PCA, posterior cerebral artery. Used with permission from (240).
Figure 14. Figure 14. Representative images of CD31‐positive hippocampal capillary endothelial cells (red) in young and aged mice fed a standard diet (SD) or HFD ((A)‐(D)). Aged animals fed with a HFD showed reduced capillary length density in the CA1 region (E and F). (*p < 0.05 vs. young SD, #p < 0.05 vs. aged SD, $p < 0.05 vs. young HFD). Used with permission from (241).
Figure 15. Figure 15. Schematic representation of BBB in health and metabolic diseases. The tightly sealed monolayer of endothelial cells in BBB are achieved by tight junction and adherens junction complexes and further supported by pericytes, astrocytes, and microglia to keep components of the circulating blood separated from neurons and brain parenchyma.


Figure 1. Schematic illustration depicting the impact of metabolic diseases on structural and functional properties of cerebral circulation. Obesity, insulin resistance, and diabetes alter physiology and structure of the cerebrovasculature leading to dysregulation of cerebral blood flow (CBF) as well as increase the risk and severity of central nervous systems complications including stroke, cognitive impairment, and neurodegeneration.


Figure 2. (A) Illustration of the carotid and vertebrobasilar arteries, main arterial supplies of the brain. (B) The arteries at the base of the brain. Internal carotid arteries (ICA) and basilar artery (BA) join to form the Circle of Willis which gives rise to cerebral arteries: anterior (ACA), middle (MCA), and posterior (PCA) cerebral arteries. Used with permission from (189).


Figure 3. Representative illustration of the angioarchitecture of the cortex demonstrating the top level of surface arteries and arterioles feeding into the subsurface capillary network via penetrating arterioles. Modified and used with permission from (94).


Figure 4. Illustration of the mechanisms of myogenic tone development. Pressure increase in the arterial wall is sensed by mechanoreceptors leading to an increase in intracellular Ca2+. Subsequently, myosin light chain kinase (MLCK) is activated leading to myosin phosphorylation and actin polymerization culminating in vasoconstriction. Rapid dephosphorylation of myosin heavy chain by myosin light chain phosphatase (MLCP) promotes relaxation. Activation of Rho‐associated kinase (ROCK) inhibits MLCP and contributes to sustained contraction. Modified and used with permission from (249).


Figure 5. (A) MCA isolated from (10–12 week) diabetic rats experienced increased myogenic tone compared to control. (*p < 0.05 vs. control, n = 6‐8). Used with permission from (139). (B) Twenty‐two‐week‐old diabetic rats experienced impaired myogenic reactivity compared to age‐matched control rats. Treatment with azilsartan restored myogenic tone of diabetic rats. (*p < 0.05 vs. Wis, #p < 0.05 vs. vehicle, n = 6‐8/group). Modified with permission from (2).


Figure 6. The working model for vasculoneuronal coupling. Increased luminal pressure causes constriction of parenchymal arteriole leading to increased Ca2+ in astrocytes via the activation of TRPV4 channels. This signal contributes to maintenance of vascular tone as well as inhibition of pyramidal neuron firing activity. It is postulated that pressure‐evoked parenchymal arteriole constriction and increased astrocytic Ca2+ can further modulate pyramidal neuron resting activity via somatostatin interneurons (dotted lines). Modified with permission from (141).


Figure 7. (A) Representative image of CBF in both diabetic and control rats generated by magnetic resonance imaging. Scale bar for color‐coding is shown below. (B) CBF was reduced in the parietal cortex and striatum of diabetic rats compared to control. (C) Time course of cortical laser‐Doppler flow in both control and diabetic rats during whisker stimulation in anesthetized animals. (D) Bar graph showing the increase in CBF during whisker stimulation, which was significantly reduced in diabetic versus control rat. (*p < 0.05 vs. cortex; p < 0.001 vs. control, n = 4‐12). Modified with permission from (139).


Figure 8. CBF is different in early and late stage diabetic mice. Representative images of cortical perfusion obtained with laser speckle (A) and whole brain perfusion obtained with MRI FAIR‐RARE (B) imaging are shown on top and collective data are summarized in bar graphs below. Laser speckle imaging reveals that at 6 weeks cortical perfusion in brain areas supplied by the MCA is decreased in diabetic animals. At 14 weeks after the onset of diabetes, diabetic mice exhibit an increase in whole‐brain perfusion compared to control mice. n = 4/group, *p < 0.05 versus control. Used with permission from (111).


Figure 9. Illustration of the angiogenesis and arteriogenesis cascade. Used with permission from (83).


Figure 10. Illustration of the retinal acellular capillary, a model of vasoregression in metabolic diseases. Acellular capillaries in the retinal vasculature are indicated by yellow arrows. Diabetes increases retinal acellular capillaries compared to control retina.


Figure 11. Glycemic control prevents deranged vascularization in diabetes. (A) Representative images of surface pial arteries in control (C), diabetes (D), and diabetes + metformin (D + M) groups. Number of collaterals quantified from these images (shown on the bar graph on the right) is significantly higher in diabetes and it is prevented by glycemic control with metformin. Mean ± SEM, n = 7 to 14, *p < 0.0001 versus C, **p < 0.001 versus D. Modified with permission from (78). Representative images showing (B) vascular branching on pial arteries and surface cortical vessels taken under 10 × and (C) inner vessel walls outlined using the Fiji software. Diabetic GK rats exhibit profound increase in branch density and diameter of pial arteries. While there was no significant change in branching of pial arteries with glycemic control, lumen diameter, and tortuosity was reduced. *p < 0.01 versus control, **p < 0.001 versus control or treatment. Mean ± SEM, n = 6 to 8. Modified with permission from (201).


Figure 12. Inhibition of VEGF signaling repairs pathological cerebral neovascularization in diabetes. Diabetic rats with established pathological neovascularization were assigned for treatment with vehicle or the VEGFR‐2 inhibitor, SLKB1002 (10 mg/kg/day) for 2 weeks. SLKB1002 significantly decreased all neovascularization indices (n = 5‐6, *, Ψp < 0.05). Used with permission from (3).


Figure 13. Illustration of blood supply to the hippocampus. The main supply to the hippocampus usually arises from the posterior circulation via single or multiple middle and posterior hippocampal arteries. ACA, anterior cerebral artery; ICA, internal carotid artery; MCA, middle cerebral artery; PcomA, posterior communicating artery; and PCA, posterior cerebral artery. Used with permission from (240).


Figure 14. Representative images of CD31‐positive hippocampal capillary endothelial cells (red) in young and aged mice fed a standard diet (SD) or HFD ((A)‐(D)). Aged animals fed with a HFD showed reduced capillary length density in the CA1 region (E and F). (*p < 0.05 vs. young SD, #p < 0.05 vs. aged SD, $p < 0.05 vs. young HFD). Used with permission from (241).


Figure 15. Schematic representation of BBB in health and metabolic diseases. The tightly sealed monolayer of endothelial cells in BBB are achieved by tight junction and adherens junction complexes and further supported by pericytes, astrocytes, and microglia to keep components of the circulating blood separated from neurons and brain parenchyma.
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Teaching Material

M. Coucha, M. Abdelsaid, R. Ward, Y. Abdul, A. Ergul. Impact of Metabolic Diseases on Cerebral Circulation: Structural and Functional Consequences. Compr Physiol. 8: 2018, 773-799.

Didactic Synopsis

Major Teaching Points:

  1. Brain has no energy reserves and depends on constant blood flow for oxygenation.
  2. Brain is a highly vascularized organ in which blood vessels are organized into three tiers: superficial pial network, penetrating arterioles, and deep microvascular network, all contributing to cerebrovascular resistance and autoregulation of cerebral blood flow (CBF).
  3. Metabolic diseases including obesity, insulin resistance, and diabetes disrupt autoregulation of CBF.
  4. Impairment of myogenic and ligand-mediated reactivity of cerebral blood arteries and arterioles as well as neurovascular coupling are the underlying causes of compromised autoregulation in metabolic diseases.
  5. Diabetes changes vascularization patterns in the brain as well as the structure of cerebral arterial tree and their interaction with neighboring cells resulting in compromised cerebrovascular architecture and integrity.
  6. Pathological changes in the structure and function of cerebral circulation contribute to development and progression of complications such as stroke and cognitive impairment in metabolic diseases.

Didactic Legends

The figures—in a freely downloadable PowerPoint format—can be found on the Images tab along with the formal legends published in the article. The following legends to the same figures are written to be useful for teaching.

Figure 1. Teaching points: Both the structure and function of blood vessels are critical for proper regulation of blood flow to the brain and BBB integrity. Changes in the structure and architecture of blood vessels involve remodeling of the vascular wall and lumen as well as the number and patterning of existing and newly formed blood vessels. Myogenic (smooth muscle cell (SMC)-derived) reactivity, vasodilatory and vasoconstrictor properties and neurovascular coupling function of cerebral vessels are important determinants of cerebrovascular function and perfusion. Metabolic diseases such as obesity, insulin resistance, and diabetes alter these properties, which can then lead to the development and/or progression of complications such as stroke and cognitive impairment.

Figure 2. Teaching points: Brain receives its arterial blood supply through two pairs of large arteries including right and left internal carotid (ICA) and vertebral arteries (VA). Branches of ICA give rise to right and left middle (MCA) and anterior (ACA) cerebral arteries as well as lenticulostriate arteries (LSA). Vertebral arteries merge to form basilar artery (BA) which gives rise to posterior cerebral artery (PCA) on both sides. In addition, right and left anterior and posterior inferior communicating arteries (AICA and PICA) and superior cerebellar artery (SCA). Branches of basilar and internal carotid arteries form the arterial circle at the base of the brain known as Circle of Willis, which was originally described by Sir Thomas Willis.

Figure 3. Teaching points: Pial arteries form a two-dimensional network at the top surface of the cortex of the brain. Penetrating arterioles stemming from pial arteries do not possess branches and dive deep into the brain tissue. Capillaries coming from these arterioles form a complex network. The components of the neurovascular unit differ across the three levels of the cerebrovascular network. At the capillary level, endothelial cells, pericytes, neurons, and astrocytes make up the neurovascular unit. Upstream in levels 2 and 3, VSMCs are also involved.

Figure 4. Teaching points: Myogenic tone development is initiated via the sensation of pressure by mechanosensors resulting in membrane depolarization. This leads to an increase in calcium influx from the extracellular space via the opening of the voltage-gated calcium channels. The increase in intracellular calcium causes: (1) myosin light chain kinase (MLCK) activation, (2) MLC phosphorylation, and (3) smooth muscle contraction. Rho kinase-mediated pathways play an important role in myogenic tone generation by phosphorylating MLC phosphatase and its inhibition. Therefore, it increases MLC phosphorylation and enhances smooth muscle contraction without further increase in intracellular calcium.

Figure 5. Teaching points: Myogenic response is an inherent property of smooth muscle cells, which aims to maintain constant blood flow despite changes in pressure. Vascular smooth muscle cells respond to pressure elevation by constriction. Myogenic response is highly pronounced in diabetes manifested by myogenic tone elevation compared to normal conditions. Enhanced myogenic tone contributes to compromised CBF reported in diabetes. However, as disease progresses upon aging, there is a significant impairment in myogenic response together with a loss of myogenic tone.

Figure 6. Teaching points: There is bidirectional communication within the components of neurovascular unit. Increased neuronal activity is coupled to vasodilation through a process known as neurovascular coupling and results in increased CBF, a response known as functional hyperemia. Parenchymal arterioles (P) can also send signals to modulate resting neuronal activity. For example, vasoconstriction induced by changes in pressure can increase Ca2+ levels in astrocytes and inhibit pyramidal neuron activity. On the other hand, dilation of arterioles increases neuronal firing activity.

Figure 7. Teaching points: The brain is a high metabolic organ, which requires a delicate balance between CBF and neuronal activity. Functional hyperemia is a vital mechanism that ensures the coupling of increased blood flow to active neurons. Cerebral blood vessels usually respond to increased neuronal activity with vasodilation, which is essential for allowing sufficient nutrient delivery and toxic by product removal at active sites. Clinical and experimental studies have shown the impairment of functional hyperemia in various pathological conditions, including diabetes and HFD. We should expect deterioration in neurovascular function once the coupling of activity and CBF is compromised.

Figure 8. Teaching points: The brain is a high metabolic organ with no energy reserves and depends on constant blood flow for proper function. Alterations in CBF, either decrease or increase, can impact brain function. Reductions in cerebral perfusion have been described in both diabetic patients as well as animal models. It was also postulated that this decrease in cerebral perfusion may be contributing to amplified cognitive decline in the diabetic subjects. On the other hand, studies in T1D patients with long-term diabetes as well as STZ-induced experimental models have also demonstrated an increase in cerebral perfusion. Thus, there may be a reversal from hypoperfusion to hyperperfusion as diabetes progresses. Decreased perfusion has been shown to lead to impaired cerebral autoregulation which in turn results in cerebral hyperperfusion due to an inability to respond to alterations in perfusion pressure.

Figure 9. Teaching points: Angiogenesis, formation of new vessels from existing ones, differs from arteriogenesis, transformation of existing vessels into larger vessels, in the initiation and the cascade of events. The left panel illustrate the sequence of the angiogenesis. Angiogenesis starts with extracellular matrix and basement membrane degradation in response to tissue hypoxia (A). The transcription factor HIF-1α is stabilized and stimulates the transcription of growth factors VEGF-A, VEGFR-2, FGF, and MMPs that stimulates endothelial cells (pink) proliferation and migration (B). Pericytes (blue) detach away from endothelial cells. The nearest endothelial cell to the highest gradient for VEGF transforms to tip cells that guide the following endothelial cells, stalk cells, toward the hypoxic tissue. Stalk cells proliferate and migrate forming a tube-like structure (C). In the final stages of the vessel maturation, pericyte recruitment promotes maturation and vessel stabilization (D). The right panel illustrates the arteriogenesis cascade. Hemodynamic forces and increased shear stress in collaterals activate vascular endothelium to proliferate and induce vasodilation (A). Upregulation of VCAM-1 and ICAM-1 and increased expression of MCP-1 and GM-CSF result in recruitment of monocytes (B). Monocytes transformed into macrophages secrete TNF-α and FGF that induced smooth muscle cells (SMCs) (pink cells with pink nuclei) proliferation (C). SMCs proliferation promotes outward remodeling and vessel maturation.

Figure 10. Teaching points: Vascular rarefaction and vasoregression normally takes place as a physiologic response pruning up newly formed vascular plexus. Vasoregression could also occur as a pathological response for metabolic diseases. Oxidative stress, endothelial dysfunction, inflammation, and hyperglycemia are the most accepted mechanisms for endothelial death contributing to the vasoregression observed in metabolic disorders. Retinal acellular capillary is a good and an easy marker to detect vascular rarefaction in metabolic disorders. Retinal vasculature is always considered as a window for the cerebrovasculature. Unlike peripheral vasculature, retinal and cerebrovasculature share a lot of common characteristics like the tight blood brain barrier, neuronal coupling, and the high pericyte to endothelial ratio. Metabolic disorders like obesity and diabetes have been shown to increase acellular capillaries in the retina. Acellular capillaries describe the endothelial cell death in retinal capillaries leaving only a thin layer of nonperfused basement membrane. In addition to the loss of endothelial cells, there is also an evidence for degeneration of smooth muscle cells and pericyte loss that leaves only a ghost basement membrane of the dead capillary.

Figure 11. Teaching points: Diabetes is a vascular disease. While diabetes causes decreased collateralization and angiogenesis in peripheral vasculature, in the eye and brain diabetes promotes excessive yet improper neovascularization. This pathological neovascularization involves formation of new vessels as a result of increased angiogenesis, new collaterals as a result of arteriogenesis, and remodeling of existing vessels. The surface pial vessels are tortuous and make extensive collaterals. Deep in the brain tissue there is also aberrant vascularization and branching. These changes can be prevented in animals treated with metformin to control blood glucose.

Figure 12. Teaching points: Augmented VEGF signaling in diabetes increases pathological neovascularization and BBB disruption. Increased VEGF signaling has been reported in different animal models of diabetes with an increase in VEGF production as well as increase in VEGFR-2 expression that cause a switch in the angiogenic balance toward formation of new vessels. While this increase in neovascularization may be a physiological compensatory response to brain hypoxia that occurs in diabetes, these newly formed vessels are leaky, immature, and very fragile due to lack of pericyte coverage demonstrating pathological neovascularization rather than a physiologic response. Moreover, a second hit with another ischemic insult, such as stroke, showed how fragile these vessels are as they undergo vasoregression and rarefaction. The figure shows that VEGFR-2 receptor antagonist, SKLB1002, inhibits VEGF angiogenic signaling and reduces all pathological neovascularization indices in diabetic rat.

Figure 13. Teaching points: Blood is supplied to the hippocampus primarily through posterior communicating artery PCA. A small percentage of arteries such as anterior, hippocampal artery originates from the anterior choroidal artery and supply the hippocampal head.

Figure 14. Teaching points: HFD-induced metabolic disease is a commonly used animal model. In the hippocampal formation, CA1 region is the most sensitive area to any ischemic insult suggesting vascularization is critical. To study the effect of aging and metabolic disease on vascularization of the hippocampus, young (7 month) and old (24 month) animals were fed with a standard or HFD. Capillaries were identified by their expression of CD31. Capillary density in the CA1 was decreased only in the aged HFD-fed animals.

Figure 15. Teaching points: Capillary endothelial cells are strongly connected with each other by tight junction proteins like occludin, claudin, and zona occludin1 as well as adherens junction proteins like cadherin/catenin complex and junction adhesion molecule JAM. This tight connection supported by pericytes, astrocytes, and basal lamina form a critical barrier function to maintain parenchymal microenvironment for proper functioning of neuronal circuits and synaptic transmission in the adult brain. In metabolic diseases, tight and adherens junction proteins are decreased compromising the barrier function. Furthermore, there is a decline in pericytes, retraction of astrocytic endfeet from capillary surfaces and upregulation of matrix metalloproteases (MMPs) that ultimately lead to increased BBB permeability and neuronal loss.


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How to Cite

Maha Coucha, Mohammed Abdelsaid, Rebecca Ward, Yasir Abdul, Adviye Ergul. Impact of Metabolic Diseases on Cerebral Circulation: Structural and Functional Consequences. Compr Physiol 2018, 8: 773-799. doi: 10.1002/cphy.c170019