Rho-kinase activation in endothelial cells contributes to expansion of infarction after focal cerebral ischemia
Rho-kinase activation in endothelial cells contributes to expansion of infarction after focal cerebral ischemia
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DOI：
10.1002/jnr.21375
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发表时间：
2007-08-15
影响因子：
4.2
通讯作者：
Hori, Masatsugu
中科院分区：
文献类型：
--
作者：
Yagita, Yoshiki;Kitagawa, Kazuo;Hori, Masatsugu
局灶性脑缺血后，微循环障碍会导致梗塞病灶扩大。最近，研究表明，在啮齿动物中风模型中，Rho 激酶通过下调内皮一氧化氮合酶功能参与内皮功能障碍。然而，目前尚不清楚内皮Rho激酶是否在体内被激活，或者Rho激酶的激活是否导致脑缺血后的微循环障碍。在这项研究中，我们评估了 Rho-kianse 活性的时间和空间分布以及 Rho-激酶抑制剂法舒地尔对局灶性脑缺血微循环障碍的影响。通过免疫组织化学分析 Rho 激酶底物内收蛋白的磷酸化来评估 Rho 激酶活化。诱导缺血后6小时，在缺血区域的内皮细胞中发现β-内收蛋白染色。在同一区域观察到微循环障碍和血管性血友病因子 (vWF) 内皮细胞染色增加。法舒地尔缺血后治疗可抑制内皮 Rho 激酶活化、保留微循环并抑制内皮细胞 vWF 染色。这些作用导致梗塞扩张的抑制和神经功能缺损的改善。这些发现表明，Rho 激酶在内皮细胞中被激活，并导致脑缺血时的微循环障碍。 Rho激酶抑制剂的血管保护作用可能有助于治疗缺血性中风的急性期。 (C) 2007 Wiley-Liss, Inc.
Microcirculatory disturbances contribute to the expansion of infarct lesions after focal cerebral ischemia. Recently, it was shown that Rho-kinase involves in endothelial dysfunction via down-regulation of endothelial nitric oxide synthase function in a rodent stroke model. However, it is not clear whether enclothelial Rho-kinase is activated in vivo or Rho-kinase activation contributes to microcirculatory disturbances after cerebral ischemia. In this study, we assessed the temporal and spatial profiles of Rho-kianse activity and the effect of the Rho-kinase inhibitor fasudil on microcirculatory disturbances in the focal brain ischemia. Rho-kinase activation was evaluated by analyzing the phosphorylation of adducin, a substrate of Rho-kinase, by immunohistochemistry. Staining for p-adducin was found in endothelia in the ischemic area 6 hr after induction of ischemia. Microcirculatory disturbances and increased endothelial cell staining for von Willebrand factor (vWF) were observed in the same area. Postischemic treatment with fasudil suppressed enclothelial Rho-kinase activation, preserved microcirculation, and inhibited endothelial cell vWF staining. These effects resulted in inhibition of infarct expansion and improvement of neurologic deficits. These findings indicate that Rho-kinase is activated in the enclothelial cells and contributes to microcirculatory disturbances in cerebral ischemia. The vascular protective effect of Rho-kinase inhibitors may be useful in the treatment of the acute phase of ischemic stroke. (C) 2007 Wiley-Liss, Inc.