Circulating endothelin-1 alters critical mechanisms regulating cerebral microcirculation.
Circulating endothelin-1 alters critical mechanisms regulating cerebral microcirculation.
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DOI：
10.1161/hypertensionaha.113.01761
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发表时间：
2013-10
期刊：
影响因子：
--
通讯作者：
Iadecola C
中科院分区：
文献类型：
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作者：
Faraco G;Moraga A;Moore J;Anrather J;Pickel VM;Iadecola C
内皮素-1（ET-1）是一种强有力的血管收缩肽，与脑卒中、蛛网膜下腔出血和脑外伤中发生的脑血管改变有关。脑和/或循环水平的ET 1升高，在这些条件和脑血管疾病的危险因素。大多数关于ET 1脑血管效应的研究都集中在血管平滑肌收缩上，而对该肽在脑血管调节中的作用知之甚少。我们验证了ET 1通过干扰调节脑血流的关键机制增加脑血管风险的假设。配备有颅窗的雄性C57 B16/J小鼠静脉内输注载体或ET 1，并通过激光多普勒血流仪评估体感皮质血流。ET 1输注增加了平均动脉压，并减弱了神经活动（晶须刺激）或内皮依赖性血管扩张剂乙酰胆碱的新皮层应用产生的血流量增加，但不是A23187。ET 1的脑血管效应被ETAR拮抗剂BQ 123消除，并且与血管氧化应激无关。相反，功能障碍依赖于Rho激酶（ROCK）活性。此外，体外研究表明，ET 1抑制内皮NO的产生，通过其代谢产物亚硝酸盐评估，与ROCK依赖的内皮一氧化氮合酶（eNOS）的磷酸化状态的变化相关的影响。总的来说，这些新的观察结果表明，增加ET 1血浆水平改变脑循环的关键调节机制，通过调节eNOS磷酸化和NO生产通过ROCK。ET 1诱导的脑血管功能障碍可能通过降低脑血管储备和增加脑对脑缺血的脆弱性来增加脑血管风险。
Endothelin-1 (ET1) is a potent vasoconstrictor peptide implicated in the cerebrovascular alterations occurring in stroke, subarachnoid hemorrhage, and brain trauma. Brain and/or circulating levels of ET1 are elevated in these conditions and in risk factors for cerebrovascular diseases. Most studies on the cerebrovascular effects of ET1 have focused on vascular smooth muscle constriction, and little is known on the effect of the peptide on cerebrovascular regulation. We tested the hypothesis that ET1 increases cerebrovascular risk by disrupting critical mechanisms regulating cerebral blood flow. Male C57Bl6/J mice equipped with a cranial window were infused intravenously with vehicle or ET1 and somatosensory cortex blood flow was assessed by laser-Doppler flowmetry. ET1 infusion increased mean arterial pressure and attenuated the blood flow increase produced by neural activity (whisker stimulation) or neocortical application of the endothelium-dependent vasodilator acetylcholine, but not A23187. The cerebrovascular effects of ET1 were abrogated by the ETAR antagonist BQ123 and were not related to vascular oxidative stress. Rather, the dysfunction was dependent on Rho Kinase (ROCK) activity. Furthermore, in vitro studies demonstrated that ET1 suppresses endothelial NO production, assessed by its metabolite nitrite, an effect associated with ROCK-dependent changes in the phosphorylation state of endothelial nitric oxide synthase (eNOS). Collectively, these novel observations demonstrate that increased ET1 plasma levels alter key regulatory mechanisms of the cerebral circulation by modulating eNOS phosphorylation and NO production through ROCK. The ET1-induced cerebrovascular dysfunction may increase cerebrovascular risk by lowering cerebrovascular reserves and increasing the vulnerability of the brain to cerebral ischemia.