Changes in Cerebral Arteries and Parenchymal Arterioles With Aging: Role of Rho Kinase 2 and Impact of Genetic Background

Vascular aging fundamentally contributes to large and small vessel disease. Despite the importance of such changes for brain function, mechanisms that mediate such changes are poorly defined. We explored mechanisms that underlie changes with age, testing the hypothesis that ROCK (Rho kinase) plays a...

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Published in:Hypertension (Dallas, Tex. 1979) Tex. 1979), 2018-05, Vol.71 (5), p.921-927
Main Authors: De Silva, T Michael, Modrick, Mary L, Dabertrand, Fabrice, Faraci, Frank M
Format: Article
Language:English
Subjects:
Aging - genetics
Analysis of Variance
Animals
Arterioles - metabolism
Cerebral Arteries - metabolism
Endothelium, Vascular - metabolism
Genetic Background
Male
Mice
Mice, Inbred C57BL
Muscle, Smooth, Vascular - metabolism
Nitric Oxide - metabolism
rho-Associated Kinases - genetics
Sensitivity and Specificity
Vascular Diseases - genetics
Vascular Diseases - physiopathology
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container_title Hypertension (Dallas, Tex. 1979)
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creator De Silva, T Michael
Modrick, Mary L
Dabertrand, Fabrice
Faraci, Frank M
description Vascular aging fundamentally contributes to large and small vessel disease. Despite the importance of such changes for brain function, mechanisms that mediate such changes are poorly defined. We explored mechanisms that underlie changes with age, testing the hypothesis that ROCK (Rho kinase) plays an important role. In C57BL/6 mice, baseline diameters of isolated pressurized parenchymal arterioles were similar in adult (4–5 month) and old mice (22±1 month; ≈15±1 µm). Endothelium-dependent dilation was impaired in old mice compared with adults in a pathway-specific manner. Vasodilation to NS-309 (which activates small- and intermediate-conductance Ca activated K channels in endothelial cells) was intact while endothelial nitric oxide synthase–mediated vasodilation was reduced by ≥60%, depending on the concentration (P
doi_str_mv 10.1161/HYPERTENSIONAHA.118.10865
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Despite the importance of such changes for brain function, mechanisms that mediate such changes are poorly defined. We explored mechanisms that underlie changes with age, testing the hypothesis that ROCK (Rho kinase) plays an important role. In C57BL/6 mice, baseline diameters of isolated pressurized parenchymal arterioles were similar in adult (4–5 month) and old mice (22±1 month; ≈15±1 µm). Endothelium-dependent dilation was impaired in old mice compared with adults in a pathway-specific manner. Vasodilation to NS-309 (which activates small- and intermediate-conductance Ca activated K channels in endothelial cells) was intact while endothelial nitric oxide synthase–mediated vasodilation was reduced by ≥60%, depending on the concentration (P&lt;0.05). A similar reduction was present in basilar arteries. Inhibiting both ROCK isoforms with Y-27632 restored the majority of endothelial function in old mice. Because genetic background is a determinant of vascular disease, we performed similar studies using FVB/N mice. Endothelial dysfunction was seen with aging in both FVB/N and C57BL/6 mice although the magnitude was increased ≈2-fold in the latter strain (P&lt;0.05). In both strains of mice, age-induced endothelial dysfunction was reversed by inhibition of ROCK2 with SLX-2119. Thus, aging impairs endothelial function in both cerebral arteries and parenchymal arterioles, predominantly via effects on endothelial nitric oxide synthase–dependent regulation of vascular tone. 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subjects Aging - genetics
Analysis of Variance
Animals
Arterioles - metabolism
Cerebral Arteries - metabolism
Endothelium, Vascular - metabolism
Genetic Background
Male
Mice
Mice, Inbred C57BL
Muscle, Smooth, Vascular - metabolism
Nitric Oxide - metabolism
rho-Associated Kinases - genetics
Sensitivity and Specificity
Vascular Diseases - genetics
Vascular Diseases - physiopathology
title Changes in Cerebral Arteries and Parenchymal Arterioles With Aging: Role of Rho Kinase 2 and Impact of Genetic Background
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