Changes in Cerebral Arteries and Parenchymal Arterioles With Aging: Role of Rho Kinase 2 and Impact of Genetic Background.
Changes in Cerebral Arteries and Parenchymal Arterioles With Aging: Role of Rho Kinase 2 and Impact of Genetic Background.
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DOI：
10.1161/hypertensionaha.118.10865
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发表时间：
2018-05
期刊：
影响因子：
--
通讯作者：
Faraci FM
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文献类型：
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作者：
De Silva TM;Modrick ML;Dabertrand F;Faraci FM
血管老化从根本上导致大血管和小血管疾病。尽管这些变化对大脑功能很重要，但介导这些变化的机制却很难定义。我们探索了随年龄变化的机制，验证了Rho激酶（ROCK）发挥重要作用的假设。在C57 BL/6小鼠中，成年小鼠（4-5个月）和老年小鼠（22±1个月）的分离加压实质小动脉的基线直径相似（约15±1微米）。与成年小鼠相比，老年小鼠的内皮依赖性扩张以特定途径的方式受损。NS-309（其激活内皮细胞中的小电导和中电导Ca 2+激活的K+通道）的血管舒张是完整的，而内皮一氧化氮（NO）合酶（eNOS）介导的血管舒张减少了60%或更多，这取决于浓度（p<0.05）。基底动脉也有类似的减少。用Y-27632抑制两种ROCK亚型恢复了老年小鼠的大部分内皮功能。由于遗传背景是血管疾病的决定因素，我们使用FVB/N小鼠进行了类似的研究。在FVB/N和C57 BL/6小鼠中均观察到内皮功能障碍，尽管在后一种品系中程度增加了几乎2倍（p<0.05）。在这两种小鼠品系中，通过SLX-2119抑制ROCK 2可逆转年龄诱导的内皮功能障碍。因此，衰老损害脑动脉和实质小动脉的内皮功能，主要是通过影响eNOS依赖的血管张力调节。这些变化的幅度受遗传背景的影响，并由ROCK 2介导。
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 Rho kinase (ROCK) plays an important role. In C57BL/6 mice, baseline diameter of isolated pressurized parenchymal arterioles were similar in adult (4–5 month) and old mice (22±1 month)(~15±1 microns). Endothelium-dependent dilation was impaired in old mice compared to adults in a pathway-specific manner. Vasodilation to NS-309 (which activates small- and intermediate-conductance Ca2+ activated K+ channels in endothelial cells) was intact, while endothelial nitric oxide (NO) synthase (eNOS)-mediated vasodilation was reduced by 60% or more, depending on the concentration (p<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 almost 2-fold in the latter strain (p<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 eNOS-dependent regulation of vascular tone. The magnitude of these changes was influenced by genetic background and mediated by ROCK2.