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Endothelial Cells and the Cerebral Circulation

Theresa A. Lansdell, Laura C. Chambers, Anne M. Dorrance

10.1002/cphy.c210015

Source: Volume 12, Issue 3, July 2022

Published online: June 2022

Full Article on Wiley Online Library



Abstract

Endothelial cells form the innermost layer of all blood vessels and are the only vascular component that remains throughout all vascular segments. The cerebral vasculature has several unique properties not found in the peripheral circulation; this requires that the cerebral endothelium be considered as a unique entity. Cerebral endothelial cells perform several functions vital for brain health. The cerebral vasculature is responsible for protecting the brain from external threats carried in the blood. The endothelial cells are central to this requirement as they form the basis of the blood‐brain barrier. The endothelium also regulates fibrinolysis, thrombosis, platelet activation, vascular permeability, metabolism, catabolism, inflammation, and white cell trafficking. Endothelial cells regulate the changes in vascular structure caused by angiogenesis and artery remodeling. Further, the endothelium contributes to vascular tone, allowing proper perfusion of the brain which has high energy demands and no energy stores. In this article, we discuss the basic anatomy and physiology of the cerebral endothelium. Where appropriate, we discuss the detrimental effects of high blood pressure on the cerebral endothelium and the contribution of cerebrovascular disease endothelial dysfunction and dementia. © 2022 American Physiological Society. Compr Physiol 12:3449‐3508, 2022.

Figure 1. Figure 1. Cerebral endothelial functions and signaling molecules produced by the endothelial cells. Servier Medical Art. Retrieved from https://servier.com/Powerpoint‐image‐bank. Licensed under CC BY‐3.0.
Figure 2. Figure 2. Cerebrovascular anatomy. The neurovascular unit (center) with a representation of a parenchymal arteriole (left) and a capillary (right). The neurovascular unit is composed of VSMC, endothelial cells, astrocytes, pericytes, and neurons. Parenchymal arterioles have a layer of endothelial cells surrounded by a single layer of smooth muscle cells, which provides the contractile machinery for the arteriole. The endothelium regulates the contractile state of the smooth muscle cells through dilatory mechanisms involving NO, TRPV4, PGE2, NMDAR, TRPA1, and TRPV3. Capillaries contain pericytes in lieu of smooth muscle cells to regulate their contractile state. Important dilatory mechanisms in capillary endothelial cells include KIR2.1, TRPV4, and TRPA1. Activation of these mechanisms in capillaries results in an upward flowing hyperpolarization that reaches the arterioles, ultimately increasing local blood flow. Parenchymal arterioles and capillaries each interact with astrocytic end feet, which acts as a liaison between neurons and the vascular system. Adapted from “Brain Vascular System”, 2021, by BioRender.com.
Figure 3. Figure 3. (A) Representative image of a cerebral myoendothelial projection. Myoendothelial projections span between endothelial cells and vascular smooth muscle cells through the internal elastic lamina and are important point of localization for vascular constriction and dilatory factors. Nearby MEPs are GqPCRs that, when activated by agonists such as carbachol (CCh), trigger the breakdown of phosphatidylinositol 4,5‐bisphosphate (PIP2) to form diacylglycerol (DAG) and inositol 1,4,5‐trisphosphate (IP3). IP3 goes on to activate IP3 receptors on the endoplasmic reticulum to induce the release of internal Ca2+ stores. DAG activates protein kinase C (PKC), which interacts with A‐kinase anchoring protein 150 (AKAP150) to assist in anchoring transient receptor potential vanilloid 4 (TRPV4) channels to the MEP. This anchoring mechanism is inhibited by hypertension. Activation of TRPV4 channels initiates an influx of Ca2+ into the endothelial cell, which then activates the nearby intermediate‐conductance Ca2+‐activated K+ channels (IKCa) to hyperpolarize the endothelial cell. This hyperpolarization crosses through gap junctions to the VSMCs, resulting in vasodilation. Vasodilation in VSMCs can be initiated by K+ influx through inwardly rectifying K+ channels (KIR) and Na+/K+ ATPase, causing the closing of voltage‐dependent Ca2+ channels. Reproduced, with permission, from Bagher P and Garland CJ, 2014 39. (B) The images were taken from mesenteric arteries, which show endothelial projections in close apposition to VSMC. Transmission electron microscopy images were obtained from third‐order mesenteric resistance arteries (a,c). Tracings of cellular structures highlight the endothelial cell (EC; dark pink), internal elastic lamina (IEL; green), smooth muscle cell (SMC; dark blue), and endoplasmic reticulum (ER; white). (b,d) Mitochondria (orange) are present at the base of the endothelial projection; caveolae (yellow) and ER‐like structures (white; vesicles gray) are visible. Reproduced from Maarouf N, et al., 2017 473.
Figure 4. Figure 4. Endothelial tight junctions and the BBB. Tight junctions between cerebrovascular endothelial cells prevent the passage of cells and molecules from the blood to the brain parenchyma. Tight junctions are formed from intracellularly linked occludin, claudin, and JAM proteins that are linked to the endothelial cell actin cytoskeleton via ZO proteins. Reproduced, with permission, from Mastorakos P and McGavern D, 2019 490.
Figure 5. Figure 5. The Glycocalyx. (A) Scanning electron micrographs showing the ultrastructure of capillaries in the brain. Upper panels: without lanthanum nitrate staining. Lower panels: with lanthanum nitrate staining to visualize the glycocalyx. Panels on the right are expanded views of those on the left. Reproduced from Ando Y, et al., 2018 29. (B) Schematic of the functions of the endothelial glycocalyx. The endothelial glycocalyx senses changes in blood flow and transduces the signal to the cytoskeleton of the endothelial cell, resulting in the production of NO and vasodilation. The glycocalyx also acts as a barrier in front of endothelial cell surface adhesion molecules to prevent recruitment of leukocytes from the blood. The glycocalyx acts as a molecular sieve by entangling blood proteins and macromolecules before they reach the endothelial cell surface. Servier Medical Art. Retrieved from https://servier.com/Powerpoint‐image‐bank. Licensed under CC BY‐3.0.
Figure 6. Figure 6. Caveolae in the cerebral vasculature. Pseudocolored electron microscopy image of a cerebral capillary (A) showing the capillary endothelial cell (cEC; purple), pericyte (teal), astrocyte end foot (blue), red blood cell (RBC; red), lumen (L; white), and neuropil (yellow). The lower part of this panel shows an inverted zoomed image of the section in the box above. Panel (B) shows a pseudocolored electron microscopy image of a cerebral arteriole. Arteriolar endothelial cell (aEC; purple), smooth muscle cell (SMC; green), astrocyte end foot (blue), and neuropil (yellow). Bottom shows a zoomed image of boxed area above. In both images, the pink arrowheads point to vesicles. Panel (C) shows electron microscopy images of arteriolar endothelial and VSMC from mice with normal caveolin expression (Cav1+/+) and caveolin knockout mice (Cav1−/−) with arrowheads identifying the caveolae. Panel (D) shows the vesicular density between capillary and arteriolar endothelial cells from wild‐type mice (n = 5 mice, 46 capillaries, and 24 arterioles). Panels (E) and (F) show the mean vesicular density in arteriolar endothelial cells (E) and VSMCs (F) between Cav1+/+ (n = 5 mice, 20 arterioles) and Cav1−/− mice (n = 5 mice, 28 arterioles). Statistical significance was determined by nested, unpaired, two‐tailed t‐test for (D‐F). Data are shown as mean ± standard error of the mean. Reproduced, with permission, from Chow BW, et al., 2020 125.
Figure 7. Figure 7. Endothelial cell‐mediated control of thrombosis. The coagulation pathway begins with the activation of either the extrinsic or intrinsic pathway that initiates a series of proteolytic steps that ultimately lead to the production of thrombin. Endothelial cells express inhibitors of thrombosis that prevent the production of thrombin. Once activated, endothelial cells play a role in the generation of thrombin through the expression of factors that promote thrombin generation. Reproduced, with permission, from Yau JW, et al., 2015 858. Licensed under CC BY 4.0.
Figure 8. Figure 8. Myogenic tone generation in mouse cerebral parenchymal arterioles. Panel (A) shows representative images for mouse parenchymal arterioles. The left image was taken immediately after increasing the intraluminal pressure to 40 mmHg prior to tone generation; the lumen diameter of the arteriole is 27 μm. The right image was taken once myogenic tone was stable; the lumen diameter was 16 μm. A representative image of the lumen diameter tracing is shown as an example, and the lumen diameters of the parenchymal arterioles are included in the images. Panel (B) shows the effects of hypertension on myogenic tone generation in parenchymal arterioles from mice. Sixteen‐week‐old C57Bl/6 male mice were treated with angiotensin II (800 ng/kg/min) for 4 weeks to induce hypertension; these were compared to control sham mice that were normotensive. The parenchymal arterioles from the hypertensive mice generated significantly more myogenic tone than their normotensive counterparts (* indicates P < 0.05 by Students t‐test). Modified, with permission, from Diaz‐Otero JM, et al., 2018 179.
Figure 9. Figure 9. Dilation in response to muscarinic receptor activation in parenchymal arterioles is mediated by TRPV4 activation. Twenty‐week‐old male C56Bl/6 mice were used. Parenchymal arteriole endothelium‐dependent dilation was assessed by pressure myography. The carbachol‐mediated dilation was not altered by N‐nitro‐l‐arginine methyl ester (L‐NAME) (100 μM) + indomethacin (Indo) (10 μM) (A), but it was impaired by GSK2193874 (B). Arteries were inhibited with various inhibitors for 20 min prior to beginning the carbachol concentration response curve. *P < 0.05 by two‐way ANOVA. Modified, with permission, from Diaz‐Otero JM, et al., 2018 179.
Figure 10. Figure 10. Hypertension impairs endothelium‐dependent parenchymal arteriole dilation. Sixteen‐week‐old male C56Bl/6 mice were treated with AngII (800 ng/kg/min) for 4 weeks; control mice were sham operated. Parenchymal arterioles were mounted in a pressure myograph system, and myogenic tone was allowed to generate. Once tone was stable, arterioles were exposed to increasing concentrations of carbachol or GSK1016790A, a specific transient receptor potential vanilloid 4 channel agonist, and vasodilator responses were compared. Both carbachol‐ and GSK1016790A‐mediated dilation was impaired in the mice made hypertensive with AngII. Modified, with permission, from Diaz‐Otero JM, et al., 2018 179.


Figure 1. Cerebral endothelial functions and signaling molecules produced by the endothelial cells. Servier Medical Art. Retrieved from https://servier.com/Powerpoint‐image‐bank. Licensed under CC BY‐3.0.


Figure 2. Cerebrovascular anatomy. The neurovascular unit (center) with a representation of a parenchymal arteriole (left) and a capillary (right). The neurovascular unit is composed of VSMC, endothelial cells, astrocytes, pericytes, and neurons. Parenchymal arterioles have a layer of endothelial cells surrounded by a single layer of smooth muscle cells, which provides the contractile machinery for the arteriole. The endothelium regulates the contractile state of the smooth muscle cells through dilatory mechanisms involving NO, TRPV4, PGE2, NMDAR, TRPA1, and TRPV3. Capillaries contain pericytes in lieu of smooth muscle cells to regulate their contractile state. Important dilatory mechanisms in capillary endothelial cells include KIR2.1, TRPV4, and TRPA1. Activation of these mechanisms in capillaries results in an upward flowing hyperpolarization that reaches the arterioles, ultimately increasing local blood flow. Parenchymal arterioles and capillaries each interact with astrocytic end feet, which acts as a liaison between neurons and the vascular system. Adapted from “Brain Vascular System”, 2021, by BioRender.com.


Figure 3. (A) Representative image of a cerebral myoendothelial projection. Myoendothelial projections span between endothelial cells and vascular smooth muscle cells through the internal elastic lamina and are important point of localization for vascular constriction and dilatory factors. Nearby MEPs are GqPCRs that, when activated by agonists such as carbachol (CCh), trigger the breakdown of phosphatidylinositol 4,5‐bisphosphate (PIP2) to form diacylglycerol (DAG) and inositol 1,4,5‐trisphosphate (IP3). IP3 goes on to activate IP3 receptors on the endoplasmic reticulum to induce the release of internal Ca2+ stores. DAG activates protein kinase C (PKC), which interacts with A‐kinase anchoring protein 150 (AKAP150) to assist in anchoring transient receptor potential vanilloid 4 (TRPV4) channels to the MEP. This anchoring mechanism is inhibited by hypertension. Activation of TRPV4 channels initiates an influx of Ca2+ into the endothelial cell, which then activates the nearby intermediate‐conductance Ca2+‐activated K+ channels (IKCa) to hyperpolarize the endothelial cell. This hyperpolarization crosses through gap junctions to the VSMCs, resulting in vasodilation. Vasodilation in VSMCs can be initiated by K+ influx through inwardly rectifying K+ channels (KIR) and Na+/K+ ATPase, causing the closing of voltage‐dependent Ca2+ channels. Reproduced, with permission, from Bagher P and Garland CJ, 2014 39. (B) The images were taken from mesenteric arteries, which show endothelial projections in close apposition to VSMC. Transmission electron microscopy images were obtained from third‐order mesenteric resistance arteries (a,c). Tracings of cellular structures highlight the endothelial cell (EC; dark pink), internal elastic lamina (IEL; green), smooth muscle cell (SMC; dark blue), and endoplasmic reticulum (ER; white). (b,d) Mitochondria (orange) are present at the base of the endothelial projection; caveolae (yellow) and ER‐like structures (white; vesicles gray) are visible. Reproduced from Maarouf N, et al., 2017 473.


Figure 4. Endothelial tight junctions and the BBB. Tight junctions between cerebrovascular endothelial cells prevent the passage of cells and molecules from the blood to the brain parenchyma. Tight junctions are formed from intracellularly linked occludin, claudin, and JAM proteins that are linked to the endothelial cell actin cytoskeleton via ZO proteins. Reproduced, with permission, from Mastorakos P and McGavern D, 2019 490.


Figure 5. The Glycocalyx. (A) Scanning electron micrographs showing the ultrastructure of capillaries in the brain. Upper panels: without lanthanum nitrate staining. Lower panels: with lanthanum nitrate staining to visualize the glycocalyx. Panels on the right are expanded views of those on the left. Reproduced from Ando Y, et al., 2018 29. (B) Schematic of the functions of the endothelial glycocalyx. The endothelial glycocalyx senses changes in blood flow and transduces the signal to the cytoskeleton of the endothelial cell, resulting in the production of NO and vasodilation. The glycocalyx also acts as a barrier in front of endothelial cell surface adhesion molecules to prevent recruitment of leukocytes from the blood. The glycocalyx acts as a molecular sieve by entangling blood proteins and macromolecules before they reach the endothelial cell surface. Servier Medical Art. Retrieved from https://servier.com/Powerpoint‐image‐bank. Licensed under CC BY‐3.0.


Figure 6. Caveolae in the cerebral vasculature. Pseudocolored electron microscopy image of a cerebral capillary (A) showing the capillary endothelial cell (cEC; purple), pericyte (teal), astrocyte end foot (blue), red blood cell (RBC; red), lumen (L; white), and neuropil (yellow). The lower part of this panel shows an inverted zoomed image of the section in the box above. Panel (B) shows a pseudocolored electron microscopy image of a cerebral arteriole. Arteriolar endothelial cell (aEC; purple), smooth muscle cell (SMC; green), astrocyte end foot (blue), and neuropil (yellow). Bottom shows a zoomed image of boxed area above. In both images, the pink arrowheads point to vesicles. Panel (C) shows electron microscopy images of arteriolar endothelial and VSMC from mice with normal caveolin expression (Cav1+/+) and caveolin knockout mice (Cav1−/−) with arrowheads identifying the caveolae. Panel (D) shows the vesicular density between capillary and arteriolar endothelial cells from wild‐type mice (n = 5 mice, 46 capillaries, and 24 arterioles). Panels (E) and (F) show the mean vesicular density in arteriolar endothelial cells (E) and VSMCs (F) between Cav1+/+ (n = 5 mice, 20 arterioles) and Cav1−/− mice (n = 5 mice, 28 arterioles). Statistical significance was determined by nested, unpaired, two‐tailed t‐test for (D‐F). Data are shown as mean ± standard error of the mean. Reproduced, with permission, from Chow BW, et al., 2020 125.


Figure 7. Endothelial cell‐mediated control of thrombosis. The coagulation pathway begins with the activation of either the extrinsic or intrinsic pathway that initiates a series of proteolytic steps that ultimately lead to the production of thrombin. Endothelial cells express inhibitors of thrombosis that prevent the production of thrombin. Once activated, endothelial cells play a role in the generation of thrombin through the expression of factors that promote thrombin generation. Reproduced, with permission, from Yau JW, et al., 2015 858. Licensed under CC BY 4.0.


Figure 8. Myogenic tone generation in mouse cerebral parenchymal arterioles. Panel (A) shows representative images for mouse parenchymal arterioles. The left image was taken immediately after increasing the intraluminal pressure to 40 mmHg prior to tone generation; the lumen diameter of the arteriole is 27 μm. The right image was taken once myogenic tone was stable; the lumen diameter was 16 μm. A representative image of the lumen diameter tracing is shown as an example, and the lumen diameters of the parenchymal arterioles are included in the images. Panel (B) shows the effects of hypertension on myogenic tone generation in parenchymal arterioles from mice. Sixteen‐week‐old C57Bl/6 male mice were treated with angiotensin II (800 ng/kg/min) for 4 weeks to induce hypertension; these were compared to control sham mice that were normotensive. The parenchymal arterioles from the hypertensive mice generated significantly more myogenic tone than their normotensive counterparts (* indicates P < 0.05 by Students t‐test). Modified, with permission, from Diaz‐Otero JM, et al., 2018 179.


Figure 9. Dilation in response to muscarinic receptor activation in parenchymal arterioles is mediated by TRPV4 activation. Twenty‐week‐old male C56Bl/6 mice were used. Parenchymal arteriole endothelium‐dependent dilation was assessed by pressure myography. The carbachol‐mediated dilation was not altered by N‐nitro‐l‐arginine methyl ester (L‐NAME) (100 μM) + indomethacin (Indo) (10 μM) (A), but it was impaired by GSK2193874 (B). Arteries were inhibited with various inhibitors for 20 min prior to beginning the carbachol concentration response curve. *P < 0.05 by two‐way ANOVA. Modified, with permission, from Diaz‐Otero JM, et al., 2018 179.


Figure 10. Hypertension impairs endothelium‐dependent parenchymal arteriole dilation. Sixteen‐week‐old male C56Bl/6 mice were treated with AngII (800 ng/kg/min) for 4 weeks; control mice were sham operated. Parenchymal arterioles were mounted in a pressure myograph system, and myogenic tone was allowed to generate. Once tone was stable, arterioles were exposed to increasing concentrations of carbachol or GSK1016790A, a specific transient receptor potential vanilloid 4 channel agonist, and vasodilator responses were compared. Both carbachol‐ and GSK1016790A‐mediated dilation was impaired in the mice made hypertensive with AngII. Modified, with permission, from Diaz‐Otero JM, et al., 2018 179.
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Article Title: Endothelial Cells and the Cerebral Circulation
 

How to Cite

Theresa A. Lansdell, Laura C. Chambers, Anne M. Dorrance. Endothelial Cells and the Cerebral Circulation. Compr Physiol 2022, 12: 3449-3508. doi: 10.1002/cphy.c210015