Comprehensive Physiology Wiley Online Library
For Librarians For Authors Editors About

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

Maha Coucha, Mohammed Abdelsaid, Rebecca Ward, Yasir Abdul, Adviye Ergul

10.1002/cphy.c170019

Source: Volume 8, Issue 2, April 2018

Published online: March 2018

Full Article on Wiley Online Library



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.

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. 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.
References
 1.Abd‐Elrahman KS, Colinas O, Walsh EJ, Zhu HL, Campbell CM, Walsh MP, Cole WC. Abnormal myosin phosphatase targeting subunit 1 phosphorylation and actin polymerization contribute to impaired myogenic regulation of cerebral arterial diameter in the type 2 diabetic Goto‐Kakizaki rat. J Cereb Blood Flow Met 37: 227‐240, 2017.
 2.Abdelsaid M, Coucha M, Ergul A. Cerebrovasculoprotective effects of azilsartan medoxomil in diabetes. Transl Res 164: 424‐432, 2014.
 3.Abdelsaid M, Coucha M, Hafez S, Yasir A, Johnson MH, Ergul A. Enhanced VEGF signalling mediates cerebral neovascularisation via downregulation of guidance protein ROBO4 in a rat model of diabetes. Diabetologia 60: 740‐750, 2017.
 4.Abdelsaid M, Kaczmarek J, Coucha M, Ergul A. Dual endothelin receptor antagonism with bosentan reverses established vascular remodeling and dysfunctional angiogenesis in diabetic rats: Relevance to glycemic control. Life Sci 118: 268‐273, 2014.
 5.Abdelsaid M, Ma H, Coucha M, Ergul A. Late dual endothelin receptor blockade with bosentan restores impaired cerebrovascular function in diabetes. Life Sci 118: 263‐267, 2014.
 6.Abdelsaid M, Prakash R, Li W, Coucha M, Hafez S, Johnson MH, Fagan SC, Ergul A. Metformin treatment in the period after stroke prevents nitrative stress and restores angiogenic signaling in the brain in diabetes. Diabetes 64: 1804‐1817, 2015.
 7.Aggarwal A, Khera A, Singh I, Sandhir R. S‐nitrosoglutathione prevents blood‐brain barrier disruption associated with increased matrix metalloproteinase‐9 activity in experimental diabetes. J Neurochem 132: 595‐608, 2015.
 8.Ahnstedt H, Sweet J, Cruden P, Bishop N, Cipolla MJ. Effects of early post‐ischemic reperfusion and tPA on cerebrovascular function and nitrosative stress in female rats. Transl Stroke Res 7: 228‐238, 2016.
 9.Alomar F, Singh J, Jang HS, Rozanzki GJ, Shao CH, Padanilam BJ, Mayhan WG, Bidasee KR. Smooth muscle‐generated methylglyoxal impairs endothelial cell‐mediated vasodilatation of cerebral microvessels in type 1 diabetic rats. Br J Pharmacol 173(23): 3307‐3326, 2016.
 10.Armulik A, Genove G, Betsholtz C. Pericytes: Developmental, physiological, and pathological perspectives, problems, and promises. Dev Cell 21: 193‐215, 2011.
 11.Armulik A, Genove G, Mae M, Nisancioglu MH, Wallgard E, Niaudet C, He L, Norlin J, Lindblom P, Strittmatter K, Johansson BR, Betsholtz C. Pericytes regulate the blood‐brain barrier. Nature 468: 557‐561, 2010.
 12.Arrick DM, Mayhan WG. Inhibition of endothelin‐1 receptors improves impaired nitric oxide synthase‐dependent dilation of cerebral arterioles in type‐1 diabetic rats. Microcirc 17: 439‐446, 2010.
 13.Arrick DM, Sharpe GM, Sun H, Mayhan WG. Diabetes‐induced cerebrovascular dysfunction: Role of poly(ADP‐ribose) polymerase. Microvasc Res 73: 1‐6, 2007.
 14.Arrick DM, Sharpe GM, Sun H, Mayhan WG. nNOS‐dependent reactivity of cerebral arterioles in type 1 diabetes. Brain Res 1184: 365‐371, 2007.
 15.Arrick DM, Sun H, Patel KP, Mayhan WG. Chronic resveratrol treatment restores vascular responsiveness of cerebral arterioles in type 1 diabetic rats. Am J Physiol 301: H696‐H703, 2011.
 16.American Diabetes Association. Diabetes Statistics. http://www.diabetes.org/diabetes‐basics/statistics. 2017.
 17.American Heart Association. Heart disease and stroke statistics‐2017 Update: A report from the American Heart Association. http://circ.ahajournals.org/content/early/2017/01/25/CIR.0000000000000485 2017.
 18.Attwell D, Buchan AM, Charpak S, Lauritzen M, Macvicar BA, Newman EA. Glial and neuronal control of brain blood flow. Nature 468: 232‐243, 2010.
 19.Bayliss WM. On the local reactions of the arterial wall to changes of internal pressure. J Physiol 28: 220‐231, 1902.
 20.Beason‐Held LL, Thambisetty M, Deib G, Sojkova J, Landman BA, Zonderman AB, Ferrucci L, Kraut MA, Resnick SM. Baseline cardiovascular risk predicts subsequent changes in resting brain function. Stroke 43: 1542‐1547, 2012.
 21.Beauquis J, Homo‐Delarche F, Giroix MH, Ehses J, Coulaud J, Roig P, Portha B, De Nicola AF, Saravia F. Hippocampal neurovascular and hypothalamic‐pituitary‐adrenal axis alterations in spontaneously type 2 diabetic GK rats. Exp Neurol 222: 125‐134, 2010.
 22.Begley DJ, Brightman MW. Structural and functional aspects of the blood‐brain barrier. Prog Drug Res 61: 39‐78, 2003.
 23.Bell RD, Winkler EA, Sagare AP, Singh I, LaRue B, Deane R, Zlokovic BV. Pericytes control key neurovascular functions and neuronal phenotype in the adult brain and during brain aging. Neuron 68: 409‐427, 2010.
 24.Bentsen N, Larsen B, Lassen NA. Chronically impaired autoregulation of cerebral blood flow in long‐term diabetics. Stroke 6: 497‐502, 1975.
 25.Berczi V, Greene AS, Dornyei G, Csengody J, Hodi G, Kadar A, Monos E. Venous myogenic tone: Studies in human and canine vessels. Am J Physiol 263: H315‐H320, 1992.
 26.Blum M, Kloos C, Gunther S, Hunger‐Dathe W, Muller UA. Improved metabolic control results in better myogenic response of retinal arterioles in patients with diabetes mellitus type 1. Ophthalmologica. Zeitschrift fur Augenheilkunde 222: 373‐377, 2008.
 27.Bor‐Seng‐Shu E, Kita WS, Figueiredo EG, Paiva WS, Fonoff ET, Teixeira MJ, Panerai RB. Cerebral hemodynamics: Concepts of clinical importance. Arq Neuropsiquiatr 70: 352‐356, 2012.
 28.Brzezinska AK, Gebremedhin D, Chilian WM, Kalyanaraman B, Elliott SJ. Peroxynitrite reversibly inhibits Ca(2+)‐activated K(+) channels in rat cerebral artery smooth muscle cells. Am J Physiol 278: H1883‐H1890, 2000.
 29.Busch SA, Silver J. The role of extracellular matrix in CNS regeneration. Curr Opin Neurobiol 17: 120‐127, 2007.
 30.Butcher JT, Goodwill AG, Stanley SC, Frisbee JC. Differential impact of dilator stimuli on increased myogenic activation of cerebral and skeletal muscle resistance arterioles in obese zucker rats. Microcirc 20: 579‐589, 2013.
 31.Cai W, Schaper W. Mechanisms of arteriogenesis. Acta Biochim Biophys Sin 40: 681‐692, 2008.
 32.Carmeliet P, Jain RK. Molecular mechanisms and clinical applications of angiogenesis. Nature 473: 298‐307, 2011.
 33.Carmignoto G, Gomez‐Gonzalo M. The contribution of astrocyte signalling to neurovascular coupling. Brain Res Rev 63: 138‐148, 2010.
 34.Catita J, Lopez‐Luppo M, Ramos D, Nacher V, Navarro M, Carretero A, Sanchez‐Chardi A, Mendes‐Jorge L, Rodriguez‐Baeza A, Ruberte J. Imaging of cellular aging in human retinal blood vessels. Exp Eye Res 135: 14‐25, 2015.
 35.Chandra SB, Mohan S, Ford BM, Huang L, Janardhanan P, Deo KS, Cong L, Muir ER, Duong TQ. Targeted overexpression of endothelial nitric oxide synthase in endothelial cells improves cerebrovascular reactivity in Ins2Akita‐type‐1 diabetic mice. J Blood Flow Met 36: 1135‐1142, 2016.
 36.Cipolla MJ. The Cerebral Circulation (2nd ed). Morgan & Claypool Life Scicnces, 2016.
 37.Cipolla MJ, Bullinger LV. Reactivity of brain parenchymal arterioles after ischemia and reperfusion. Microcirc 15: 495‐501, 2008.
 38.Cipolla MJ, Curry AB. Middle cerebral artery function after stroke: The threshold duration of reperfusion for myogenic activity. Stroke 33: 2094‐2099, 2002.
 39.Cipolla MJ, Godfrey JA. Effect of hyperglycemia on brain penetrating arterioles and cerebral blood flow before and after ischemia/reperfusion. Transl Stroke Res 1: 127‐134, 2010.
 40.Cipolla MJ, Gokina NI, Osol G. Pressure‐induced actin polymerization in vascular smooth muscle as a mechanism underlying myogenic behavior. FASEB J 16: 72‐76, 2002.
 41.Cipolla MJ, Lessov N, Hammer ES, Curry AB. Threshold duration of ischemia for myogenic tone in middle cerebral arteries: Effect on vascular smooth muscle actin. Stroke 32: 1658‐1664, 2001.
 42.Cipolla MJ, Li R, Vitullo L. Perivascular innervation of penetrating brain parenchymal arterioles. J CardiovascPharmacol 44: 1‐8, 2004.
 43.Cipolla MJ, Osol G. Vascular smooth muscle actin cytoskeleton in cerebral artery forced dilatation. Stroke 29: 1223‐1228, 1998.
 44.Cipolla MJ, Porter JM, Osol G. High glucose concentrations dilate cerebral arteries and diminish myogenic tone through an endothelial mechanism. Stroke 28: 405‐410; discussion 410‐401, 1997.
 45.Cipolla MJ, Smith J, Kohlmeyer MM, Godfrey JA. SKCa and IKCa Channels, myogenic tone, and vasodilator responses in middle cerebral arteries and parenchymal arterioles: Effect of ischemia and reperfusion. Stroke 40: 1451‐1457, 2009.
 46.Cipolla MJ, Sweet J, Chan SL, Tavares MJ, Gokina N, Brayden JE. Increased pressure‐induced tone in rat parenchymal arterioles vs. middle cerebral arteries: Role of ion channels and calcium sensitivity. J Appl Physiol 117: 53‐59, 2014.
 47.Cipolla MJ, Sweet JG, Gokina NI, White SL, Nelson MT. Mechanisms of enhanced basal tone of brain parenchymal arterioles during early postischemic reperfusion: Role of ET‐1‐induced peroxynitrite generation. J Cereb Blood Flow Met 33: 1486‐1492, 2013.
 48.Coucha M, Li W, Hafez S, Abdelsaid M, Johnson MH, Fagan SC, Ergul A. SOD1 overexpression prevents acute hyperglycemia‐induced cerebral myogenic dysfunction: Relevance to contralateral hemisphere and stroke outcomes. Am J Physiol 308: H456‐H466, 2015.
 49.Coucha M, Li W, Johnson MH, Fagan SC, Ergul A. Protein nitration impairs the myogenic tone of rat middle cerebral arteries in both ischemic and nonischemic hemispheres after ischemic stroke. Am J Physiol 305: H1726‐H1735, 2013.
 50.Coyle P. Vascular patterns of the rat hippocampal formation. Exp Neurol 52: 447‐458, 1976.
 51.Czeh B, Abumaria N, Rygula R, Fuchs E. Quantitative changes in hippocampal microvasculature of chronically stressed rats: No effect of fluoxetine treatment. Hippocampus 20: 174‐185, 2010.
 52.Dalkara T, Gursoy‐Ozdemir Y, Yemisci M. Brain microvascular pericytes in health and disease. Acta Neuropathol 122: 1‐9, 2011.
 53.Daneman R, Zhou L, Kebede AA, Barres BA. Pericytes are required for blood‐brain barrier integrity during embryogenesis. Nature 468: 562‐566, 2010.
 54.Davidson TL, Hargrave SL, Swithers SE, Sample CH, Fu X, Kinzig KP, Zheng W. Inter‐relationships among diet, obesity and hippocampal‐dependent cognitive function. Neurosci 253: 110‐122, 2013.
 55.Davidson TL, Monnot A, Neal AU, Martin AA, Horton JJ, Zheng W. The effects of a high‐energy diet on hippocampal‐dependent discrimination performance and blood‐brain barrier integrity differ for diet‐induced obese and diet‐resistant rats. Physiol Behav 107: 26‐33, 2012.
 56.Davis MJ. Myogenic response gradient in an arteriolar network. Am J Physiol 264: H2168‐H2179, 1993.
 57.Davis MJ, Hill MA. Signaling mechanisms underlying the vascular myogenic response. Physiologic Rev 79: 387‐423, 1999.
 58.Davis CM, Siler DA, Alkayed NJ. Endothelium‐derived hyperpolarizing factor in the brain: Influence of sex, vessel size and disease state. Women Health 7: 293‐303, 2011.
 59.de Senna PN, Xavier LL, Bagatini PB, Saur L, Galland F, Zanotto C, Bernardi C, Nardin P, Goncalves CA, Achaval M. Physical training improves non‐spatial memory, locomotor skills and the blood brain barrier in diabetic rats. Brain Res 1618: 75‐82, 2015.
 60.De Silva TM, Faraci FM. Microvascular dysfunction and cognitive impairment. Cell Mol Neurobiol 36: 241‐258, 2016.
 61.Deryugina EI, Quigley JP. Pleiotropic roles of matrix metalloproteinases in tumor angiogenesis: Contrasting, overlapping and compensatory functions. Biochimica Biophysica Acta 1803: 103‐120, 2010.
 62.Deutsch C, Portik‐Dobos V, Smith AD, Ergul A, Dorrance AM. Diet‐induced obesity causes cerebral vessel remodeling and increases the damage caused by ischemic stroke. Microvasc Res 78: 100‐106, 2009.
 63.Didion SP, Faraci FM. Effects of NADH and NADPH on superoxide levels and cerebral vascular tone. Am J Physiol 282: H688‐H695, 2002.
 64.Didion SP, Lynch CM, Baumbach GL, Faraci FM. Impaired endothelium‐dependent responses and enhanced influence of Rho‐kinase in cerebral arterioles in type II diabetes. Stroke 36: 342‐347, 2005.
 65.Ding J, Strachan MW, Fowkes FG, Wong TY, Macgillivray TJ, Patton N, Gardiner TA, Deary IJ, Price JF. Association of retinal arteriolar dilatation with lower verbal memory: The Edinburgh type 2 diabetes study. Diabetologia 54: 1653‐1662, 2011.
 66.Dong L, Xie MJ, Zhang P, Ji LL, Liu WC, Dong MQ, Gao F. Rotenone partially reverses decreased BK Ca currents in cerebral artery smooth muscle cells from streptozotocin‐induced diabetic mice. Clin Exp Pharmacol Physiol 36: e57‐e64, 2009.
 67.Dong L, Zheng YM, Van Riper D, Rathore R, Liu QH, Singer HA, Wang YX. Functional and molecular evidence for impairment of calcium‐activated potassium channels in type‐1 diabetic cerebral artery smooth muscle cells. J Cereb Blood Flow Met 28: 377‐386, 2008.
 68.Dorner GT, Garhofer G, Huemer KH, Riva CE, Wolzt M, Schmetterer L. Hyperglycemia affects flicker‐induced vasodilation in the retina of healthy subjects. Vis Res 43: 1495‐1500, 2003.
 69.Dornyei G, Monos E, Kaley G, Koller A. Myogenic responses of isolated rat skeletal muscle venules: Modulation by norepinephrine and endothelium. Am J Physiol 271: H267‐H272, 1996.
 70.Dorrance AM, Matin N, Pires PW. The effects of obesity on the cerebral vasculature. Curr Vasc Pharmacol 12: 462‐472, 2014.
 71.Drake CJ. Embryonic and adult vasculogenesis. Birth Defects Res C Embryo Today 69: 73‐82, 2003.
 72.Drake CT, Iadecola C. The role of neuronal signaling in controlling cerebral blood flow. Brain Lang 102: 141‐152, 2007.
 73.Driscoll JD, Shih AY, Drew PJ, Cauwenberghs G, Kleinfeld D. Two‐photon imaging of blood flow in the rat cortex. Cold Spring Harb Protoc 2013: 759‐767, 2013.
 74.Duarte JV, Pereira JM, Quendera B, Raimundo M, Moreno C, Gomes L, Carrilho F, Castelo‐Branco M. Early disrupted neurovascular coupling and changed event level hemodynamic response function in type 2 diabetes: An fMRI study. J Blood Flow Met 35: 1671‐1680, 2015.
 75.Duckrow RB, Beard DC, Brennan RW. Regional cerebral blood flow decreases during chronic and acute hyperglycemia. Stroke 18: 52‐58, 1987.
 76.Dumont AS, Dumont RJ, McNeill JH, Kassell NF, Sutherland GR, Verma S. Chronic endothelin antagonism restores cerebrovascular function in diabetes. Neurosurg 52: 653‐660; discussion 659‐660, 2003.
 77.Elgebaly MM, Ogbi S, Li W, Mezzetti EM, Prakash R, Johnson MH, Bruno A, Fagan SC, Ergul A. Neurovascular injury in acute hyperglycemia and diabetes: A comparative analysis in experimental stroke. Transl Stroke Res 2: 391‐398, 2011.
 78.Elgebaly MM, Prakash R, Li W, Ogbi S, Johnson MH, Mezzetti EM, Fagan SC, Ergul A. Vascular protection in diabetic stroke: Role of matrix metalloprotease‐dependent vascular remodeling. J Blood Flow Met 30: 1928‐1938, 2010.
 79.Elliott SJ, Lacey DJ, Chilian WM, Brzezinska AK. Peroxynitrite is a contractile agonist of cerebral artery smooth muscle cells. Am J Physiol 275: H1585‐H1591, 1998.
 80.Erdem A, Yasargil G, Roth P. Microsurgical anatomy of the hippocampal arteries. J Neurosurg 79: 256‐265, 1993.
 81.Erdos B, Snipes JA, Miller AW, Busija DW. Cerebrovascular dysfunction in Zucker obese rats is mediated by oxidative stress and protein kinase C. Diabetes 53: 1352‐1359, 2004.
 82.Erdos B, Snipes JA, Tulbert CD, Katakam P, Miller AW, Busija DW. Rosuvastatin improves cerebrovascular function in Zucker obese rats by inhibiting NAD(P)H oxidase‐dependent superoxide production. Am J Physiol 290: H1264‐H1270, 2006.
 83.Ergul A, Abdelsaid M, Fouda AY, Fagan SC. Cerebral neovascularization in diabetes: Implications for stroke recovery and beyond. J Blood Flow Met 34: 553‐563, 2014.
 84.Ergul A, Alhusban A, Fagan SC. Angiogenesis: A harmonized target for recovery after stroke. Stroke 43: 2270‐2274, 2012.
 85.Ergul A, Kelly‐Cobbs A, Abdalla M, Fagan SC. Cerebrovascular complications of diabetes: Focus on stroke. Endocr Metab Immune Disord Drug Targets 12: 148‐158, 2012.
 86.Ergul A, Valenzuela JP, Fouda AY, Fagan SC. Cellular connections, microenvironment and brain angiogenesis in diabetes: Lost communication signals in the post‐stroke period. Brain Res 1623: 81‐96, 2015.
 87.Faber JE, Moore SM, Lucitti JL, Aghajanian A, Zhang H. Sex differences in the cerebral collateral circulation. Transl Stroke Res 8(3): 273‐283, 2017.
 88.Falcone JC, Davis MJ, Meininger GA. Endothelial independence of myogenic response in isolated skeletal muscle arterioles. Am J Physiol 260: H130‐H135, 1991.
 89.Fann DY, Santro T, Manzanero S, Widiapradja A, Cheng YL, Lee SY, Chunduri P, Jo DG, Stranahan AM, Mattson MP, Arumugam TV. Intermittent fasting attenuates inflammasome activity in ischemic stroke. Exp Neurol 257: 114‐119, 2014.
 90.Faraci FM, Heistad DD. Regulation of large cerebral arteries and cerebral microvascular pressure. Circ Res 66: 8‐17, 1990.
 91.Feletou M, Vanhoutte PM. EDHF: An update. Clin Sci 117: 139‐155, 2009.
 92.Feletou M, Vanhoutte PM. Endothelium‐dependent hyperpolarization: No longer an f‐word! J Cardiovasc Pharmacol 61: 91‐92, 2013.
 93.Ferrara N. VEGF‐A: A critical regulator of blood vessel growth. Eur Cytokine Netw 20: 158‐163, 2009.
 94.Filosa JA, Morrison HW, Iddings JA, Du W, Kim KJ. Beyond neurovascular coupling, role of astrocytes in the regulation of vascular tone. Neurosci 323: 96‐109, 2016.
 95.Fu Z, Wu J, Nesil T, Li MD, Aylor KW, Liu Z. Long‐term high‐fat diet induces hippocampal microvascular insulin resistance and cognitive dysfunction. Am J Physiol 312: E89‐E97, 2017.
 96.Fujihara R, Chiba Y, Nakagawa T, Nishi N, Murakami R, Matsumoto K, Kawauchi M, Yamamoto T, Ueno M. Albumin microvascular leakage in brains with diabetes mellitus. Microsc Res Tech 79: 833‐837, 2016.
 97.Fukuda S, Nakagawa S, Tatsumi R, Morofuji Y, Takeshita T, Hayashi K, Tanaka K, Matsuo T, Niwa M. Glucagon‐like peptide‐1 strengthens the barrier integrity in primary cultures of rat brain endothelial cells under basal and hyperglycemia conditions. J Mol Neurosci 59: 211‐219, 2016.
 98.Gandhi GK, Ball KK, Cruz NF, Dienel GA. Hyperglycaemia and diabetes impair gap junctional communication among astrocytes. ASN Neuro 2: e00030, 2010.
 99.Garhofer G, Zawinka C, Resch H, Kothy P, Schmetterer L, Dorner GT. Reduced response of retinal vessel diameters to flicker stimulation in patients with diabetes. Br J Ophthalmol 88: 887‐891, 2004.
 100.Gebremedhin D, Terashvili M, Wickramasekera N, Zhang DX, Rau N, Miura H, Harder DR. Redox signaling via oxidative inactivation of PTEN modulates pressure‐dependent myogenic tone in rat middle cerebral arteries. PLoS One 8: e68498, 2013.
 101.Gibbons GH, Dzau VJ. The emerging concept of vascular remodeling. N Engl J Med 330: 1431‐1438, 1994.
 102.Girouard H, Iadecola C. Neurovascular coupling in the normal brain and in hypertension, stroke, and Alzheimer disease. J Appl Physiol 100: 328‐335, 2006.
 103.Gorelick PB, Scuteri A, Black SE, Decarli C, Greenberg SM, Iadecola C, Launer LJ, Laurent S, Lopez OL, Nyenhuis D, Petersen RC, Schneider JA, Tzourio C, Arnett DK, Bennett DA, Chui HC, Higashida RT, Lindquist R, Nilsson PM, Roman GC, Sellke FW, Seshadri S, American Heart Association Stroke Council CoE, Prevention CoCNCoCR, Intervention, Council on Cardiovascular S, and Anesthesia. Vascular contributions to cognitive impairment and dementia: A statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 42: 2672‐2713, 2011.
 104.Grivas I, Michaloudi H, Batzios C, Chiotelli M, Papatheodoropoulos C, Kostopoulos G, Papadopoulos GC. Vascular network of the rat hippocampus is not homogeneous along the septotemporal axis. Brain Res 971: 245‐249, 2003.
 105.Haast RA, Kiliaan AJ. Impact of fatty acids on brain circulation, structure and function. Prostaglandins Leukot Essent Fatty Acids 92: 3‐14, 2015.
 106.Hafez S, Coucha M, Bruno A, Fagan SC, Ergul A. Hyperglycemia, acute ischemic stroke, and thrombolytic therapy. Transl Stroke Res 5: 442‐453, 2014.
 107.Hall CN, Reynell C, Gesslein B, Hamilton NB, Mishra A, Sutherland BA, O'Farrell FM, Buchan AM, Lauritzen M, Attwell D. Capillary pericytes regulate cerebral blood flow in health and disease. Nature 508: 55‐60, 2014.
 108.Hamel E. Perivascular nerves and the regulation of cerebrovascular tone. J Appl Physiol 100: 1059‐1064, 2006.
 109.Hansen PB, De Mey JG, Vanhoutte PM. Endothelium‐dependent hyperpolarizations in health and disease. Acta Physiol 219: 97‐99, 2017.
 110.Harder DR. Pressure‐dependent membrane depolarization in cat middle cerebral artery. Circ Res 55: 197‐202, 1984.
 111.Hardigan T, Hernandez C, Ward R, Hoda MN, Ergul A. TLR2 knockout protects against diabetes‐mediated changes in cerebral perfusion and cognitive deficits. Am J Physiol 312(6): R927‐R937, 2017.
 112.Hardigan T, Ward R, Ergul A. Cerebrovascular complications of diabetes: Focus on cognitive dysfunction. Clin Sci 130: 1807‐1822, 2016.
 113.Hargrave SL, Davidson TL, Zheng W, Kinzig KP. Western diets induce blood‐brain barrier leakage and alter spatial strategies in rats. Behav Neurosci 130: 123‐135, 2016.
 114.Harris AK, Elgebaly MM, Li W, Sachidanandam K, Ergul A. Effect of chronic endothelin receptor antagonism on cerebrovascular function in type 2 diabetes. Am J Physiol 294: R1213‐R1219, 2008.
 115.Harris AK, Hutchinson JR, Sachidanandam K, Johnson MH, Dorrance AM, Stepp DW, Fagan SC, Ergul A. Type 2 diabetes causes remodeling of cerebrovasculature via differential regulation of matrix metalloproteinases and collagen synthesis: Role of endothelin‐1. Diabetes 54: 2638‐2644, 2005.
 116.Hawkins BT, Lundeen TF, Norwood KM, Brooks HL, Egleton RD. Increased blood‐brain barrier permeability and altered tight junctions in experimental diabetes in the rat: Contribution of hyperglycaemia and matrix metalloproteinases. Diabetologia 50: 202‐211, 2007.
 117.Heil M, Eitenmuller I, Schmitz‐Rixen T, Schaper W. Arteriogenesis versus angiogenesis: Similarities and differences. J Cell Mol Med 10: 45‐55, 2006.
 118.Heistad DD, Marcus ML, Abboud FM. Role of large arteries in regulation of cerebral blood flow in dogs. Clin Invest 62: 761‐768, 1978.
 119.Hirano K. Current topics in the regulatory mechanism underlying the Ca2+ sensitization of the contractile apparatus in vascular smooth muscle. J Pharmacol Sci 104: 109‐115, 2007.
 120.Howitt L, Sandow SL, Grayson TH, Ellis ZE, Morris MJ, Murphy TV. Differential effects of diet‐induced obesity on BKCa {beta}1‐subunit expression and function in rat skeletal muscle arterioles and small cerebral arteries. Am J Physiol 301: H29‐H40, 2011.
 121.Hu J, Liu B, Zhao Q, Jin P, Hua F, Zhang Z, Liu Y, Zan K, Cui G, Ye X. Bone marrow stromal cells inhibits HMGB1‐mediated inflammation after stroke in type 2 diabetic rats. Neurosci 324: 11‐19, 2016.
 122.Hu X, De Silva TM, Chen J, Faraci FM. Cerebral vascular disease and neurovascular injury in ischemic stroke. Circ Res 120: 449‐471, 2017.
 123.Huang JY, Li LT, Wang H, Liu SS, Lu YM, Liao MH, Tao RR, Hong LJ, Fukunaga K, Chen Z, Wilcox CS, Lai EY, Han F. In vivo two‐photon fluorescence microscopy reveals disturbed cerebral capillary blood flow and increased susceptibility to ischemic insults in diabetic mice. CNS Neurosci Ther 20: 816‐822, 2014.
 124.Iadecola C, Nedergaard M. Glial regulation of the cerebral microvasculature. Nature Neurosci 10: 1369‐1376, 2007.
 125.Iadecola C, Yang G, Ebner TJ, Chen G. Local and propagated vascular responses evoked by focal synaptic activity in cerebellar cortex. J Neurophysiol 78: 651‐659, 1997.
 126.Iida Y, Katusic ZS. Mechanisms of cerebral arterial relaxations to hydrogen peroxide. Stroke 31: 2224‐2230, 2000.
 127.Institoris A, Lenti L, Domoki F, Wappler E, Gaspar T, Katakam PV, Bari F, Busija DW. Cerebral microcirculatory responses of insulin‐resistant rats are preserved to physiological and pharmacological stimuli. Microcirc 19: 749‐756, 2012.
 128.Jarajapu YP, Guberski DL, Grant MB, Knot HJ. Myogenic tone and reactivity of cerebral arteries in type II diabetic BBZDR/Wor rat. Eur J Pharmacol 579: 298‐307, 2008.
 129.Jimenez‐Bonilla JF, Quirce R, Hernandez A, Vallina NK, Guede C, Banzo I, Amado JA, Carril JM. Assessment of cerebral perfusion and cerebrovascular reserve in insulin‐dependent diabetic patients without central neurological symptoms by means of 99mTc‐HMPAO SPET with acetazolamide. Eur J Nucl Med 28: 1647‐1655, 2001.
 130.Johnson PC. Autoregulation of blood flow. Circ Res 59: 483‐495, 1986.
 131.Johnson PC. Myogenic nature of increase in intestinal vascular resistance with venous pressure elevation. Circ Res 7: 992‐999, 1959.
 132.Kanoski SE, Zhang Y, Zheng W, Davidson TL. The effects of a high‐energy diet on hippocampal function and blood‐brain barrier integrity in the rat. J Alzheimers Dis 21: 207‐219, 2010.
 133.Karagiannis J, Reid JJ, Darby I, Roche P, Rand MJ, Li CG. Impaired nitric oxide function in the basilar artery of the obese Zucker rat. J Cardiovasc Pharmacol 42: 497‐505, 2003.
 134.Katakam PV, Domoki F, Snipes JA, Busija AR, Jarajapu YP, Busija DW. Impaired mitochondria‐dependent vasodilation in cerebral arteries of Zucker obese rats with insulin resistance. Am J Physiol 296: R289‐R298, 2009.
 135.Katakam PV, Wappler EA, Katz PS, Rutkai I, Institoris A, Domoki F, Gaspar T, Grovenburg SM, Snipes JA, Busija DW. Depolarization of mitochondria in endothelial cells promotes cerebral artery vasodilation by activation of nitric oxide synthase. Arterioscl Thrombosis Vascul Bio 33: 752‐759, 2013.
 136.Katusic ZS, Schugel J, Cosentino F, Vanhoutte PM. Endothelium‐dependent contractions to oxygen‐derived free radicals in the canine basilar artery. Am J Physiol 264: H859‐H864, 1993.
 137.Kelly‐Cobbs A, Elgebaly MM, Li W, Ergul A. Pressure‐independent cerebrovascular remodelling and changes in myogenic reactivity in diabetic Goto‐Kakizaki rat in response to glycaemic control. Acta Physiol 203: 245‐251, 2011.
 138.Kelly‐Cobbs AI, Harris AK, Elgebaly MM, Li W, Sachidanandam K, Portik‐Dobos V, Johnson M, Ergul A. Endothelial endothelin B receptor‐mediated prevention of cerebrovascular remodeling is attenuated in diabetes because of up‐regulation of smooth muscle endothelin receptors. J Pharmacol Exp Ther 337: 9‐15, 2011.
 139.Kelly‐Cobbs AI, Prakash R, Coucha M, Knight RA, Li W, Ogbi SN, Johnson M, Ergul A. Cerebral myogenic reactivity and blood flow in type 2 diabetic rats: Role of peroxynitrite in hypoxia‐mediated loss of myogenic tone. J Pharmacol Exp Ther 342: 407‐415, 2012.
 140.Kim DW, Glendining KA, Grattan DR, Jasoni CL. Maternal obesity in the mouse compromises the blood‐brain barrier in the arcuate nucleus of offspring. Endocrinol 157: 2229‐2242, 2016.
 141.Kim KJ, Ramiro Diaz J, Iddings JA, Filosa JA. Vasculo‐neuronal coupling: Retrograde vascular communication to brain neurons. J Neurosci 36: 12624‐12639, 2016.
 142.Kim YS, Immink RV, Stok WJ, Karemaker JM, Secher NH, van Lieshout JJ. Dynamic cerebral autoregulatory capacity is affected early in type 2 diabetes. Clin Sci 115: 255‐262, 2008.
 143.Kirino T. Delayed neuronal death in the gerbil hippocampus following ischemia. Brain Res 239: 57‐69, 1982.
 144.Kisler K, Nelson AR, Rege SV, Ramanathan A, Wang Y, Ahuja A, Lazic D, Tsai PS, Zhao Z, Zhou Y, Boas DA, Sakadzic S, Zlokovic BV. Pericyte degeneration leads to neurovascular uncoupling and limits oxygen supply to brain. Nature Neurosci 20: 406‐416, 2017.
 145.Kitayama J, Faraci FM, Gunnett CA, Heistad DD. Impairment of dilator responses of cerebral arterioles during diabetes mellitus: Role of inducible NO synthase. Stroke 37: 2129‐2133, 2006.
 146.Knierim JJ. The hippocampus. Curr Biol 25: R1116‐R1121, 2015.
 147.Knot HJ, Nelson MT. Regulation of arterial diameter and wall [Ca2+] in cerebral arteries of rat by membrane potential and intravascular pressure. J Physiol 508(Pt 1): 199‐209, 1998.
 148.Knot HJ, Nelson MT. Regulation of membrane potential and diameter by voltage‐dependent K+ channels in rabbit myogenic cerebral arteries. Am J Physiol 269: H348‐H355, 1995.
 149.Knot HJ, Standen NB, Nelson MT. Ryanodine receptors regulate arterial diameter and wall [Ca2+] in cerebral arteries of rat via Ca2+‐dependent K+ channels. J Physiol 508(Pt 1): 211‐221, 1998.
 150.Kold‐Petersen H, Brondum E, Nilsson H, Flyvbjerg A, Aalkjaer C. Impaired myogenic tone in isolated cerebral and coronary resistance arteries from the goto‐kakizaki rat model of type 2 diabetes. J Vasc Res 49: 267‐278, 2012.
 151.Koller A, Toth P. Contribution of flow‐dependent vasomotor mechanisms to the autoregulation of cerebral blood flow. J Vasc Res 49: 375‐389, 2012.
 152.Kowianski P, Lietzau G, Steliga A, Waskow M, Morys J. The astrocytic contribution to neurovascular coupling–‐Still more questions than answers? Neurosci Res 5: 171‐183, 2013.
 153.Kumari R, Willing LB, Patel SD, Baskerville KA, Simpson IA. Increased cerebral matrix metalloprotease‐9 activity is associated with compromised recovery in the diabetic db/db mouse following a stroke. J Neurochem 119: 1029‐1040, 2011.
 154.Kuo L, Chilian WM, Davis MJ. Coronary arteriolar myogenic response is independent of endothelium. Circ Res 66: 860‐866, 1990.
 155.Last D, Alsop DC, Abduljalil AM, Marquis RP, de Bazelaire C, Hu K, Cavallerano J, Novak V. Global and regional effects of type 2 diabetes on brain tissue volumes and cerebral vasoreactivity. Diabetes Care 30: 1193‐1199, 2007.
 156.Li J, Li W, Altura BT, Altura BM. Peroxynitrite‐induced relaxation in isolated canine cerebral arteries and mechanisms of action. Toxicol Appl Pharmacol 196: 176‐182, 2004.
 157.Li J, Li W, Altura BT, Altura BM. Peroxynitrite‐induced relaxation in isolated rat aortic rings and mechanisms of action. Toxicol Appl Pharmacol 209: 269‐276, 2005.
 158.Li W, Prakash R, Chawla D, Du W, Didion SP, Filosa JA, Zhang Q, Brann DW, Lima VV, Tostes RC, Ergul A. Early effects of high‐fat diet on neurovascular function and focal ischemic brain injury. Am J Physiol 304: R1001‐R1008, 2013.
 159.Li W, Prakash R, Kelly‐Cobbs AI, Ogbi S, Kozak A, El‐Remessy AB, Schreihofer DA, Fagan SC, Ergul A. Adaptive cerebral neovascularization in a model of type 2 diabetes: Relevance to focal cerebral ischemia. Diabetes 59: 228‐235, 2010.
 160.Li W, Sachidanandam K, Ergul A. Comparison of selective versus dual endothelin receptor antagonism on cerebrovascular dysfunction in diabetes. Neurol Res 33: 185‐191, 2011.
 161.Li XL, Aou S, Oomura Y, Hori N, Fukunaga K, Hori T. Impairment of long‐term potentiation and spatial memory in leptin receptor‐deficient rodents. Neurosci 113: 607‐615, 2002.
 162.Liu C, Wu J, Zou MH. Activation of AMP‐activated protein kinase alleviates high‐glucose‐induced dysfunction of brain microvascular endothelial cell tight‐junction dynamics. Free Radic Biol Med 53: 1213‐1221, 2012.
 163.Longden TA, Dabertrand F, Koide M, Gonzales AL, Tykocki NR, Brayden JE, Hill‐Eubanks D, Nelson MT. Capillary K+‐sensing initiates retrograde hyperpolarization to increase local cerebral blood flow. Nature Neurosci 20: 717‐726, 2017.
 164.Lynch CM, Kinzenbaw DA, Chen X, Zhan S, Mezzetti E, Filosa J, Ergul A, Faulkner JL, Faraci FM, Didion SP. Nox2‐derived superoxide contributes to cerebral vascular dysfunction in diet‐induced obesity. Stroke 44: 3195‐3201, 2013.
 165.Mandecka A, Dawczynski J, Blum M, Muller N, Kloos C, Wolf G, Vilser W, Hoyer H, Muller UA. Influence of flickering light on the retinal vessels in diabetic patients. Diabetes Care 30: 3048‐3052, 2007.
 166.Mankovsky BN, Piolot R, Mankovsky OL, Ziegler D. Impairment of cerebral autoregulation in diabetic patients with cardiovascular autonomic neuropathy and orthostatic hypotension. Diab Med 20: 119‐126, 2003.
 167.Markus HS. Cerebral perfusion and stroke. J Neurol Neurosurg Psyc 75: 353‐361, 2004.
 168.May JM, Jayagopal A, Qu ZC, Parker WH. Ascorbic acid prevents high glucose‐induced apoptosis in human brain pericytes. Biochem Biophys Res Commun 452: 112‐117, 2014.
 169.Mayhan WG, Arrick DM. Tetrahydrobiopterin rescues impaired responses of cerebral resistance arterioles during type 1 diabetes. Diab Vasc Dis Res 14: 33‐39, 2017.
 170.Mayhan WG, Arrick DM, Patel KP, Sun H. Exercise training normalizes impaired NOS‐dependent responses of cerebral arterioles in type 1 diabetic rats. Am J Physiol 300: H1013‐H1020, 2011.
 171.Mayhan WG, Arrick DM, Sharpe GM, Patel KP, Sun H. Inhibition of NAD(P)H oxidase alleviates impaired NOS‐dependent responses of pial arterioles in type 1 diabetes mellitus. Microcirc 13: 567‐575, 2006.
 172.Mayhan WG, Scott JP, Arrick DM. Influence of type 1 diabetes on basal and agonist‐induced permeability of the blood‐brain barrier. Physiol Rep 3: e12653, 2015.
 173.Mayhan WG, Trauernicht AK, Irvine SD. Insulin reverses impaired acetylcholine‐induced dilatation of the rat basilar artery during diabetes mellitus. Brain Res 893: 195‐201, 2001.
 174.McCormick M, Hadley D, McLean JR, Macfarlane JA, Condon B, Muir KW. Randomized, controlled trial of insulin for acute poststroke hyperglycemia. Ann Neurol 67: 570‐578, 2010.
 175.McCrimmon RJ, Ryan CM, Frier BM. Diabetes and cognitive dysfunction. Lancet 379: 2291‐2299, 2012.
 176.McCuskey PA, McCuskey RS. In vivo and electron microscopic study of the development of cerebral diabetic microangiography. Microcirc Endothel Lymphatics 1: 221‐244, 1984.
 177.Merdzo I, Rutkai I, Sure VN, McNulty CA, Katakam PV, Busija DW. Impaired mitochondrial respiration in large cerebral arteries of rats with type 2 diabetes. J Vasc Res 54: 1‐12, 2017.
 178.Merdzo I, Rutkai I, Tokes T, Sure VN, Katakam PV, Busija DW. The mitochondrial function of the cerebral vasculature in insulin‐resistant Zucker obese rats. Am J Physiol 310: H830‐H838, 2016.
 179.Miller FJ, Jr., Dellsperger KC, Gutterman DD. Myogenic constriction of human coronary arterioles. Am J Physiol 273: H257‐H264, 1997.
 180.Min LJ, Mogi M, Shudou M, Jing F, Tsukuda K, Ohshima K, Iwanami J, Horiuchi M. Peroxisome proliferator‐activated receptor‐gamma activation with angiotensin II type 1 receptor blockade is pivotal for the prevention of blood‐brain barrier impairment and cognitive decline in type 2 diabetic mice. Hypertension 59: 1079‐1088, 2012.
 181.Mino T, Yuasa U, Naka M, Tanaka T. Phosphorylation of calponin mediated by protein kinase C in association with contraction in porcine coronary artery. Biochem Biophys Res Commun 208: 397‐404, 1995.
 182.Mishra A, Newman EA. Inhibition of inducible nitric oxide synthase reverses the loss of functional hyperemia in diabetic retinopathy. Glia 58: 1996‐2004, 2010.
 183.Mishra A, Reynolds JP, Chen Y, Gourine AV, Rusakov DA, Attwell D. Astrocytes mediate neurovascular signaling to capillary pericytes but not to arterioles. Nature Neurosci 19: 1619‐1627, 2016.
 184.Moghaddam HK, Baluchnejadmojarad T, Roghani M, Khaksari M, Norouzi P, Ahooie M, Mahboobi F. Berberine ameliorate oxidative stress and astrogliosis in the hippocampus of STZ‐induced diabetic rats. Mol Neurobiol 49: 820‐826, 2014.
 185.Mogi M, Horiuchi M. Neurovascular coupling in cognitive impairment associated with diabetes mellitus. Circ J 75: 1042‐1048, 2011.
 186.Moore SM, Zhang H, Maeda N, Doerschuk CM, Faber JE. Cardiovascular risk factors cause premature rarefaction of the collateral circulation and greater ischemic tissue injury. Angiogenesis 18: 265‐281, 2015.
 187.Mulvany MJ, Baumbach GL, Aalkjaer C, Heagerty AM, Korsgaard N, Schiffrin EL, Heistad DD. Vascular remodeling. Hypertension 28: 505‐506, 1996.
 188.Nagamachi S, Nishikawa T, Ono S, Ageta M, Matsuo T, Jinnouchi S, Hoshi H, Ohnishi T, Futami S, Watanabe K. Regional cerebral blood flow in diabetic patients: Evaluation by N‐isopropyl‐123I‐IMP with SPECT. Nucl Med Commun 15: 455‐460, 1994.
 189.Nagata K, Yamazaki T, Takano D, Maeda T, Fujimaki Y, Nakase T, Sato Y. Cerebral circulation in aging. Ageing Res Rev 30: 49‐60, 2016.
 190.Narayanan J, Imig M, Roman RJ, Harder DR. Pressurization of isolated renal arteries increases inositol trisphosphate and diacylglycerol. Am J Physiol 266: H1840‐H1845, 1994.
 191.Nazir FS, Alem M, Small M, Connell JM, Lees KR, Walters MR, Cleland SJ. Blunted response to systemic nitric oxide synthase inhibition in the cerebral circulation of patients with type 2 diabetes. Diab Med 23: 398‐402, 2006.
 192.Nishimura N, Schaffer CB, Friedman B, Lyden PD, Kleinfeld D. Penetrating arterioles are a bottleneck in the perfusion of neocortex. Proc Natl Acad Sci U S A 104: 365‐370, 2007.
 193.Osmond JM, Mintz JD, Dalton B, Stepp DW. Obesity increases blood pressure, cerebral vascular remodeling, and severity of stroke in the Zucker rat. Hypertension 53: 381‐386, 2009.
 194.Osmond JM, Mintz JD, Stepp DW. Preventing increased blood pressure in the obese Zucker rat improves severity of stroke. Am J Physiol 299: H55‐H61, 2010.
 195.Osol G, Halpern W. Myogenic properties of cerebral blood vessels from normotensive and hypertensive rats. Am J Physiol 249: H914‐H921, 1985.
 196.Palomares SM, Cipolla MJ. Vascular protection following cerebral ischemia and reperfusion. J Neurol Neurophysiol 2011: S1‐S004, 2011.
 197.Pannasch U, Vargova L, Reingruber J, Ezan P, Holcman D, Giaume C, Sykova E, Rouach N. Astroglial networks scale synaptic activity and plasticity. Proc Natl Acad Sci U S A 108: 8467‐8472, 2011.
 198.Pantoni L GP. Cerebral Small Vessel Disease. Cambridge: Cambridge University Press, 2014.
 199.Patton N, Aslam T, Macgillivray T, Pattie A, Deary IJ, Dhillon B. Retinal vascular image analysis as a potential screening tool for cerebrovascular disease: A rationale based on homology between cerebral and retinal microvasculatures. J Anat 206: 319‐348, 2005.
 200.Phillips AA, Chan FH, Zheng MM, Krassioukov AV, Ainslie PN. Neurovascular coupling in humans: Physiology, methodological advances and clinical implications. J Cereb Blood Flow Met 36: 647‐664, 2016.
 201.Phillips SA, Sylvester FA, Frisbee JC. Oxidant stress and constrictor reactivity impair cerebral artery dilation in obese Zucker rats. Am J Physiol 288: R522‐R530, 2005.
 202.Prakash R, Johnson M, Fagan SC, Ergul A. Cerebral neovascularization and remodeling patterns in two different models of type 2 diabetes. PLoS One 8: e56264, 2013.
 203.Prakash R, Li W, Qu Z, Johnson MA, Fagan SC, Ergul A. Vascularization pattern after ischemic stroke is different in control versus diabetic rats: Relevance to stroke recovery. Stroke 44: 2875‐2882, 2013.
 204.Prakash R, Somanath PR, El‐Remessy AB, Kelly‐Cobbs A, Stern JE, Dore‐Duffy P, Johnson M, Fagan SC, Ergul A. Enhanced cerebral but not peripheral angiogenesis in the Goto‐Kakizaki model of type 2 diabetes involves VEGF and peroxynitrite signaling. Diabetes 61: 1533‐1542, 2012.
 205.Price TO, Eranki V, Banks WA, Ercal N, Shah GN. Topiramate treatment protects blood‐brain barrier pericytes from hyperglycemia‐induced oxidative damage in diabetic mice. Endocrinol 153: 362‐372, 2012.
 206.Price TO, Sheibani N, Shah GN. Regulation of high glucose‐induced apoptosis of brain pericytes by mitochondrial CA VA: A specific target for prevention of diabetic cerebrovascular pathology. Biochimica Biophysica Acta 1863: 929‐935, 2017.
 207.Quaegebeur A, Lange C, Carmeliet P. The neurovascular link in health and disease: Molecular mechanisms and therapeutic implications. Neuron 71: 406‐424, 2011.
 208.Quirce R, Carril JM, Jimenez‐Bonilla JF, Amado JA, Gutierrez‐Mendiguchia C, Banzo I, Blanco I, Uriarte I, Montero A. Semi‐quantitative assessment of cerebral blood flow with 99mTc‐HMPAO SPET in type I diabetic patients with no clinical history of cerebrovascular disease. Eur J Nucl Med 24: 1507‐1513, 1997.
 209.Reeson P, Jeffery A, Brown CE. Illuminating the effects of stroke on the diabetic brain: Insights from imaging neural and vascular networks in experimental animal models. Diabetes 65: 1779‐1788, 2016.
 210.Reeson P, Tennant KA, Gerrow K, Wang J, Weiser Novak S, Thompson K, Lockhart KL, Holmes A, Nahirney PC, Brown CE. Delayed inhibition of VEGF signaling after stroke attenuates blood‐brain barrier breakdown and improves functional recovery in a comorbidity‐dependent manner. J Neurosci 35: 5128‐5143, 2015.
 211.Rosenberg GA, Estrada EY, Dencoff JE. Matrix metalloproteinases and TIMPs are associated with blood‐brain barrier opening after reperfusion in rat brain. Stroke 29: 2189‐2195, 1998.
 212.Rosenegger DG, Gordon GR. A slow or modulatory role of astrocytes in neurovascular coupling. Microcirc 22: 197‐203, 2015.
 213.Saab BJ, Georgiou J, Nath A, Lee FJ, Wang M, Michalon A, Liu F, Mansuy IM, Roder JC. NCS‐1 in the dentate gyrus promotes exploration, synaptic plasticity, and rapid acquisition of spatial memory. Neuron 63: 643‐656, 2009.
 214.Sabri O, Hellwig D, Schreckenberger M, Schneider R, Kaiser HJ, Wagenknecht G, Mull M, Buell U. Influence of diabetes mellitus on regional cerebral glucose metabolism and regional cerebral blood flow. Nucl Med Commun 21: 19‐29, 2000.
 215.Sachidanandam K, Harris A, Hutchinson J, Ergul A. Microvascular versus macrovascular dysfunction in type 2 diabetes: Differences in contractile responses to endothelin‐1. Exp Biol Med 231: 1016‐1021, 2006.
 216.Sajja RK, Prasad S, Cucullo L. Impact of altered glycaemia on blood‐brain barrier endothelium: An in vitro study using the hCMEC/D3 cell line. Fluids Barriers CNS 11: 8, 2014.
 217.Salem MA, Matta LF, Tantawy AA, Hussein M, Gad GI. Single photon emission tomography (SPECT) study of regional cerebral blood flow in normoalbuminuric children and adolescents with type 1 diabetes. Pediatr Diabetes 3: 155‐162, 2002.
 218.Saravia FE, Revsin Y, Gonzalez Deniselle MC, Gonzalez SL, Roig P, Lima A, Homo‐Delarche F, De Nicola AF. Increased astrocyte reactivity in the hippocampus of murine models of type 1 diabetes: The nonobese diabetic (NOD) and streptozotocin‐treated mice. Brain Res 957: 345‐353, 2002.
 219.Sauve M, Hui SK, Dinh DD, Foltz WD, Momen A, Nedospasov SA, Offermanns S, Husain M, Kroetsch JT, Lidington D, Bolz SS. Tumor necrosis factor/sphingosine‐1‐phosphate signaling augments resistance artery myogenic tone in diabetes. Diabetes 65: 1916‐1928, 2016.
 220.Schaper W. Collateral circulation: Past and present. Basic Res Cardiol 104: 5‐21, 2009.
 221.Schubert R, Mulvany MJ. The myogenic response: Established facts and attractive hypotheses. Clin Sci 96: 313‐326, 1999.
 222.Schwab KO, Doerfer J, Hecker W, Grulich‐Henn J, Wiemann D, Kordonouri O, Beyer P, Holl RW, and Diabetology DPVIotGWGfP. Spectrum and prevalence of atherogenic risk factors in 27,358 children, adolescents, and young adults with type 1 diabetes: Cross‐sectional data from the German diabetes documentation and quality management system (DPV). Diab Care 29: 218‐225, 2006.
 223.Schwaninger RM, Sun H, Mayhan WG. Impaired nitric oxide synthase‐dependent dilatation of cerebral arterioles in type II diabetic rats. Life Sci 73: 3415‐3425, 2003.
 224.Selkurt EE, Johnson PC. Effect of acute elevation of portal venous pressure on mesenteric blood volume, interstitial fluid volume and hemodynamics. Circ Res 6: 592‐599, 1958.
 225.Shah GN, Morofuji Y, Banks WA, Price TO. High glucose‐induced mitochondrial respiration and reactive oxygen species in mouse cerebral pericytes is reversed by pharmacological inhibition of mitochondrial carbonic anhydrases: Implications for cerebral microvascular disease in diabetes. Biochem Biophys Res Commun 440: 354‐358, 2013.
 226.Shao B, Bayraktutan U. Hyperglycaemia promotes cerebral barrier dysfunction through activation of protein kinase C‐beta. Diabetes Obes Metab 15: 993‐999, 2013.
 227.Shih AY, Ruhlmann C, Blinder P, Devor A, Drew PJ, Friedman B, Knutsen PM, Lyden PD, Mateo C, Mellander L, Nishimura N, Schaffer CB, Tsai PS, Kleinfeld D. Robust and fragile aspects of cortical blood flow in relation to the underlying angioarchitecture. Microcirc 22: 204‐218, 2015.
 228.Sieber FE, Brown PR, Wu Y, Koehler RC, Traystman RJ. Cerebral blood flow responsivity to CO2 in anesthetized chronically diabetic dogs. Am J Physiol 264: H1069‐H1075, 1993.
 229.Simons M. Angiogenesis: Where do we stand now? Circulation 111: 1556‐1566, 2005.
 230.Sobey CG, Heistad DD, Faraci FM. Mechanisms of bradykinin‐induced cerebral vasodilatation in rats. Evidence that reactive oxygen species activate K+ channels. Stroke 28: 2290‐2294; discussion 2295, 1997.
 231.Starr JM, Wardlaw J, Ferguson K, MacLullich A, Deary IJ, Marshall I. Increased blood‐brain barrier permeability in type II diabetes demonstrated by gadolinium magnetic resonance imaging. J Neurol Neurosurg Psyc 74: 70‐76, 2003.
 232.Stranahan AM. Models and mechanisms for hippocampal dysfunction in obesity and diabetes. Neurosci 309: 125‐139, 2015.
 233.Stranahan AM, Hao S, Dey A, Yu X, Baban B. Blood‐brain barrier breakdown promotes macrophage infiltration and cognitive impairment in leptin receptor‐deficient mice. J Cereb Blood Flow Met 36: 2108‐2121, 2016.
 234.Sun D, Kaley G, Koller A. Characteristics and origin of myogenic response in isolated gracilis muscle arterioles. Am J Physiol 266: H1177‐H1183, 1994.
 235.Sun D, Messina EJ, Kaley G, Koller A. Characteristics and origin of myogenic response in isolated mesenteric arterioles. Am J Physiol y 263: H1486‐H1491, 1992.
 236.Sweeney MD, Ayyadurai S, Zlokovic BV. Pericytes of the neurovascular unit: Key functions and signaling pathways. Nature Neurosci 19: 771‐783, 2016.
 237.Sweetnam D, Holmes A, Tennant KA, Zamani A, Walle M, Jones P, Wong C, Brown CE. Diabetes impairs cortical plasticity and functional recovery following ischemic stroke. J Neurosci 32: 5132‐5143, 2012.
 238.Tennant KA, Brown CE. Diabetes augments in vivo microvascular blood flow dynamics after stroke. J Neurosci 33: 19194‐19204, 2013.
 239.Thambisetty M, Beason‐Held LL, An Y, Kraut M, Metter J, Egan J, Ferrucci L, O'Brien R, Resnick SM. Impaired glucose tolerance in midlife and longitudinal changes in brain function during aging. Neurobiol Aging 34: 2271‐2276, 2013.
 240.Thammaroj J, Santosh C, Bhattacharya J. The hippocampus: Modern imaging of its anatomy and pathology. Prac Neurol 5: 150‐155, 2005.
 241.Tucsek Z, Toth P, Tarantini S, Sosnowska D, Gautam T, Warrington JP, Giles CB, Wren JD, Koller A, Ballabh P, Sonntag WE, Ungvari Z, Csiszar A. Aging exacerbates obesity‐induced cerebromicrovascular rarefaction, neurovascular uncoupling, and cognitive decline in mice. J Gerontol A Biol Sci Med Sci 69: 1339‐1352, 2014.
 242.Uyttenboogaart M, Koch MW, Stewart RE, Vroomen PC, Luijckx GJ, De Keyser J. Moderate hyperglycaemia is associated with favourable outcome in acute lacunar stroke. Brain 130: 1626‐1630, 2007.
 243.Van Buren T, Vleeming W, Krutzen MM, Van de Kuil T, Gispen WH, De Wildt DJ. Vascular responses of isolated mesenteric resistance and basilar arteries from short‐ and long‐term diabetic rats. Naunyn‐Schmiedeberg ArchPharmacol 358: 663‐670, 1998.
 244.van Elderen SG, Brandts A, van der Grond J, Westenberg JJ, Kroft LJ, van Buchem MA, Smit JW, de Roos A. Cerebral perfusion and aortic stiffness are independent predictors of white matter brain atrophy in type 1 diabetic patients assessed with magnetic resonance imaging. Diab Care 34: 459‐463, 2011.
 245.Vandekeere S, Dewerchin M, Carmeliet P. Angiogenesis revisited: An overlooked role of endothelial cell metabolism in vessel sprouting. Microcirc 22: 509‐517, 2015.
 246.Venkat P, Chopp M, Chen J. New insights into coupling and uncoupling of cerebral blood flow and metabolism in the brain. Croatian Medical J 57: 223‐228, 2016.
 247.Vetri F, Qi M, Xu H, Oberholzer J, Paisansathan C. Impairment of neurovascular coupling in type 1 diabetes mellitus in rats is prevented by pancreatic islet transplantation and reversed by a semi‐selective PKC inhibitor. Brain Res 1655: 48‐54, 2017.
 248.Vetri F, Xu H, Paisansathan C, Pelligrino DA. Impairment of neurovascular coupling in type 1 diabetes mellitus in rats is linked to PKC modulation of BK(Ca) and Kir channels. Am J Physiol 302: H1274‐H1284, 2012.
 249.Walsh MP, Cole WC. The role of actin filament dynamics in the myogenic response of cerebral resistance arteries. J Cereb Blood Flow Met 33: 1‐12, 2013.
 250.Wang S, Zhang H, Dai X, Sealock R, Faber JE. Genetic architecture underlying variation in extent and remodeling of the collateral circulation. Circ Res 107: 558‐568, 2010.
 251.Ward R, Valenzuela JP, Ergul A. Abstract TMP115: Diabetes‐induced neuronal degeneration and dysfunctional neovascularization in the hippocampus: Implications for cognitive impairment and stroke. Stroke 47: ATMP115‐ATMP115, 2016.
 252.Webb RC. Smooth muscle contraction and relaxation. Adv Physiol Edu 27: 201‐206, 2003.
 253.Wei EP, Kontos HA, Beckman JS. Mechanisms of cerebral vasodilation by superoxide, hydrogen peroxide, and peroxynitrite. Am J Physiol 271: H1262‐H1266, 1996.
 254.Winder SJ, Walsh MP. Smooth muscle calponin. Inhibition of actomyosin MgATPase and regulation by phosphorylation. J Biol Chem 265: 10148‐10155, 1990.
 255.Winkler EA, Bell RD, Zlokovic BV. Central nervous system pericytes in health and disease. Nature Neurosci 14: 1398‐1405, 2011.
 256.Xu Z, Zeng W, Sun J, Chen W, Zhang R, Yang Z, Yao Z, Wang L, Song L, Chen Y, Zhang Y, Wang C, Gong L, Wu B, Wang T, Zheng J, Gao F. The quantification of blood‐brain barrier disruption using dynamic contrast‐enhanced magnetic resonance imaging in aging rhesus monkeys with spontaneous type 2 diabetes mellitus. Neuroimage 158: 480‐487, 2017.
 257.Yang H, Ma S, Liu Y, Li Y, Wu W, Han E, Jia G, Wang C. Poor outcome of experimental ischemic stroke in type 2 diabetic rats: Impaired circulating endothelial progenitor cells mobilization. J Stroke Cerebrovasc Dis 24: 980‐987, 2015.
 258.Ye X, Chopp M, Cui X, Zacharek A, Cui Y, Yan T, Shehadah A, Roberts C, Liu X, Lu M, Chen J. Niaspan enhances vascular remodeling after stroke in type 1 diabetic rats. Exp Neurol 232: 299‐308, 2011.
 259.Ye X, Chopp M, Liu X, Zacharek A, Cui X, Yan T, Roberts C, Chen J. Niaspan reduces high‐mobility group box 1/receptor for advanced glycation end products after stroke in type‐1 diabetic rats. Neurosci 190: 339‐345, 2011.
 260.You J, Johnson TD, Marrelli SP, Mombouli JV, Bryan RM, Jr. P2u receptor‐mediated release of endothelium‐derived relaxing factor/nitric oxide and endothelium‐derived hyperpolarizing factor from cerebrovascular endothelium in rats. Stroke 30: 1125‐1133, 1999.
 261.Zhang H, Huang M, Gao L, Lei H. Region‐specific cerebral metabolic alterations in streptozotocin‐induced type 1 diabetic rats: An in vivo proton magnetic resonance spectroscopy study. J Cereb Blood Flow Met 35: 1738‐1745, 2015.
 262.Zhang H, Prabhakar P, Sealock R, Faber JE. Wide genetic variation in the native pial collateral circulation is a major determinant of variation in severity of stroke. J Cereb Blood Flow Met 30: 923‐934, 2010.
 263.Zhang Z, Yan J, Shi H. Role of hypoxia inducible factor 1 in hyperglycemia‐exacerbated blood‐brain barrier disruption in ischemic stroke. Neurobiol Dis 95: 82‐92, 2016.
 264.Qu Z, Li W, Prakash R, Fagan SC, Ergul A. Diet‐induced diabetes impairs neovascularization and functional recovery after ischemic stroke. Stroke 45: A169, 2014.
 265.Zimmermann PA, Knot HJ, Stevenson AS, Nelson MT. Increased myogenic tone and diminished responsiveness to ATP‐sensitive K+ channel openers in cerebral arteries from diabetic rats. Circ Res 81: 996‐1004, 1997.

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.


Related Articles:

The Cerebral Microcirculation
Microvascular Consequences of Obesity and Diabetes

Contact Editor

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

* Required Field

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

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