Endothelin-1 overexpression leads to blood-brain barrier disruption, more brain edema and increased aquaporin 4 expression in astrocytic processes after experimental stroke

Abstract

Under normal condition endothelin-1 (ET-1) is expressed by cerebral endothelial cells. However, increased level of ET-1 was observed in both astrocytes and endothelial cells after experimental ischemic stroke and hypoxia/ischemia, suggesting a potential role of astrocytic and endothelial ET-1 in ischemic brain injury. Previously, we reported that transgenic mice over-expressing ET-1 in astrocytes (GET-1 mice) displayed increased cerebral infarct size and more severe neurological deficits upon focal cerebral ischemia induced by middle cerebral artery occlusion (MCAO). However, the mechanism behind astrocytic ET-1 on ischemia-induced brain injury was not clear. Here, we report that GET mice showed lower occludin levels and increased Evans blue extravasation, suggesting increased blood-brain barrier (BBB) breakdown in GET-1 mice after MCAO. GET-1 mice also displayed increased brain swelling and brain water content together with decreased occludin and up-regulated aquaporin 4 expression. These results suggested that increased astrocytic ET-1 resulted in BBB disruption leading to increased formation of brain edema and swelling, infarct and neurological deficits and therefore imposed adverse effects on brain injury after focal cerebral ischemia. Acknowledgement: Supported by Research Grants Council and Area of Excellence from University Grants Council of Hong Kong (AoE/B-15/01).