Endothelin-1 overexpression leads to further water accumulation and brain edema after middle cerebral artery occlusion via aquaporin 4 expression in astrocytic end-feet
Endothelin-1 overexpression leads to further water accumulation and brain edema after middle cerebral artery occlusion via aquaporin 4 expression in astrocytic end-feet
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DOI：
10.1038/sj.jcbfm.9600108
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发表时间：
2005-08-01
影响因子：
6.3
通讯作者：
Chung, SK
中科院分区：
文献类型：
--
作者：
Lo, ACY;Chen, AYS;Chung, SK
中风患者血浆或脑脊液中的内皮素-1 （ET-1）水平升高，内皮素-1是一种强血管收缩剂。先前我们发现，缺氧/缺血后星形胶质细胞中ET-1 mRNA的表达水平较高。目前尚不清楚ET-1诱导星形胶质细胞在脑缺血中的作用是保护还是破坏。在这里，我们建立了一个转基因小鼠模型，利用胶质纤维酸性蛋白启动子在星形胶质细胞中过表达ET-1 (GET-1)，通过对这些小鼠进行短暂性大脑中动脉闭塞（MCAO）的挑战，研究星形胶质细胞ET-1在缺血性卒中中的作用。正常情况下，GET-1小鼠的脑形态、脑血管系统、绝对脑血流量、血脑屏障（BBB）完整性、平均动脉血压均无异常。然而，短暂性MCAO的GET-1小鼠表现出更严重的神经功能缺损和梗死增加，MCAO后5分钟给予ABT-627 （ETA拮抗剂）部分正常化。此外，MCAO后GET-1脑表现出更多的Evans蓝色外渗，内皮occludin表达降低，与脑含水量升高和脑水肿增加有关。水通道蛋白4在GET-1同侧脑血管上星形细胞端足的表达也更为明显。我们目前的数据表明，星形胶质细胞ET-1对水稳态、脑水肿和血脑屏障完整性具有有害影响，从而导致更严重的缺血性脑损伤。
Stroke patients have increased levels of endothelin-1 (ET-1), a strong vasoconstrictor, in their plasma or cerebrospinal fluid. Previously, we showed high level of ET-1 mRNA expression in astrocytes after hypoxia/ischemia. It is unclear whether the contribution of ET-1 induction in astrocytes is protective or destructive in cerebral ischemia. Here, we generated a transgenic mouse model that overexpress ET-1 in astrocytes (GET-1) using the glial fibrillary acidic protein promoter to examine the role of astrocytic ET-1 in ischemic stroke by challenging these mice with transient middle cerebral artery occlusion (MCAO). Under normal condition, GET-1 mice showed no abnormality in brain morphology, cerebrovasculature, absolute cerebral blood flow, blood-brain barrier (BBB) integrity, and mean arterial blood pressure. Yet, GET-1 mice subjected to transient MCAO showed more severe neurologic deficits and increased infarct, which were partially normalized by administration of ABT-627 (ETA antagonist) 5 mins after MCAO. In addition, GET-1 brains exhibited more Evans blue extravasation and showed decreased endothelial occludin expression after MCAO, correlating with higher brain water content and increased cerebral edema. Aquaporin 4 expression was also more pronounced in astrocytic end-feet on blood vessels in GET-1 ipsilateral brains. Our current data suggest that astrocytic ET-1 has deleterious effects on water homeostasis, cerebral edema and BBB integrity, which contribute to more severe ischemic brain injury.