脑梗死后缺血脑组织水肿是导致患者急性期死亡最重要的原因之一。我们发现: 大鼠脑梗死后3-7天为水肿高峰期，与Sema3E/Plexin-D1信号调控内皮细胞间紧密连接、血脑屏障密切相关。本项目拟在In vivo 和 In vitro 情况下, 采用磁共振灌注显像、磁共振-T1增强序列、免疫共沉淀、慢病毒转染及小分子多肽封闭等多种试验方法, 探讨脑梗死后Sema3E/Plexin-D1信号与血脑屏障破坏、渗漏增加、脑水肿的调控关系, 讨论脑梗死后, 缺血缺氧诱导神经元释放Sema3E激活Plexin-D1受体双重调控 PIP5KIβ-Arf6-ZO-1和SH3BP1-Rac1-Occludin-1信号途径, 加强内皮细胞紧密连接、保护血脑屏障的具体分子机制。探讨以Sema3E为治疗靶点, 脑梗死后减轻缺血脑组织渗漏及脑水肿体积, 降低脑梗塞急性期死亡率, 为急性期脑梗死治疗提供新策略。

The mechanism of blood-brain barrier (BBB) disruption after ischemic stroke, involved in edema and hemorrhagic transformation, is very important but elusive. Here, we investigated Sema3E mediated mechanism in the disruption of BBB after stroke in rats. We found that up-regulation of Sema3E decreased permeability of BBB as detected by Magnetic Resonance Imaging (MRI) after middle cerebral artery occlusion (MCAO) in vivo, and decreased permeability of brain microvascular endothelial cells (BMECs) after oxygen-glucose deprivation (OGD) in vitro as well. The expression of ZO-1/Occluding-1, key tight junction protein (TJP), were decreased in ischemic boundary zone (IBZ) following up-regulation of Sema3E. Moreover, in BMECs, we found that Sema3E synchronously regulated PIP5KIβ-Arf6 and SH3BP1-Rac1 signaling pathway separately to increase the expression level of claudin-5 and occluding-1. Collectively, our findings suggested that Sema3E could enhance tight junction protein (ZO-1/Occluding-1), thus, affecting the permeability of BBB after MCAO in rats, and Sema3E might be a potential alternative target for the treatment of stroke.