EGR1-Zyxin信号通路调控缺血性卒中后颅内静脉回流障碍的机制研究

Nearly half of acute ischemic stroke patients suffer reperfusion injury after receiving ultra-early reperfusion therapy. The damage after cerebral ischemia occurs in endothelium of venules, resulting in the formation of venous thrombosis, intracranial venous drainage disturbance and therefore a poor prognosis after reperfusion therapy. Early growth response factor 1 (EGR1) is one of the main initial factors created subsequent to cerebral ischemia. In our prior research, we found that the level of EGR1 in the venous endothelium increased in rats following acute middle cerebral artery occlusion. Additionally, in in vitro human umbilical vein endothelial cells, knockout of the EGR1 gene was associated with a reduction of Zyxin, which regulates the endothelium secretion of Weibel-Palade Body (WPB) in which the most abundant cargo is prothrombotic von Willebrand factor. However, the prothrombotic mechanism of the EGR1-Zyxin pathway remains unclear. Based on these previous studies, we will explore the regulation of EGR1 on the expression of Zyxin, and how the EGR1-Zyxin signal pathway regulates the process of brain venule thrombosis. Studying this will help to clarify the injury mechanism of the cerebral venous system after ischemic stroke, providing a new potential target for reperfusion therapy.

急性缺血性卒中超早期再灌注治疗后有近半数患者发生再灌注损伤。脑缺血后损伤可作用于静脉内皮诱发微静脉血栓形成，造成颅内静脉回流障碍从而影响再灌注结局。早期生长反应因子1（EGR1）是脑缺血后血管内皮迅速过表达的主要因子，前期研究中我们观察到，急性大脑中动脉闭塞可引起颅内静脉内皮EGR1表达升高，且EGR1基因敲减后可致调控Weibel-Palade小体（WPB）胞吐的斑联蛋白（Zyxin）水平降低，而恰恰WPB中主要成分为促血栓形成的血管性血友病因子，但该通路参与颅内静脉回流障碍的具体作用机制不详。本研究将在前期基础上，继续深入研究EGR1对Zyxin的调控机制，以及EGR1-Zyxin信号通路调控颅内微静脉血栓形成过程。本研究结果将有助于阐明缺血性卒中后颅内静脉系统损伤机制，为优化再灌注治疗提供潜在新靶点。

急性缺血性卒中超早期再灌注治疗后有近半数患者发生再灌注损伤。脑缺血后损伤可作用于静脉内皮诱发微静脉血栓形成，造成颅内静脉回流障碍从而影响再灌注结局。早期生长反应因子1（EGR1）是脑缺血后血管内皮迅速过表达的主要因子，前期研究中我们观察到，急性大脑中动脉闭塞可引起颅内静脉内皮EGR1表达升高，且EGR1基因敲减后可致调控Weibel-Palade小体（WPB）胞吐的斑联蛋白（Zyxin）水平降低，而恰恰WPB中主要成分为促血栓形成的血管性血友病因子，但该通路参与颅内静脉回流障碍的具体作用机制不详。本项目在研期间从细胞水平明确了HUVEC上EGR1对Zyxin的转录机制，完成了EGR1-Zyxin信号通路对静脉内皮细胞WPB胞吐调控的分析。从动物水平完成了MCAO大鼠的CTP扫描及微静脉血栓形成的观察，并完成了EGR1-Zyxin信号通路对颅内静脉血栓形成和静脉回流障碍的调控机制分析。结果证实，缺血条件条件下静脉内皮中EGR1对Zyxin具有调控转录作用，验证了缺血条件下EGR1-Zyxin信号通路对静脉内皮细胞WPB胞吐和vWF释放的调控作用，并揭示了卒中后缺血/再灌注条件下EGR1-Zyxin信号通路对微血栓形成和静脉回流障碍的调控作用。该研究结果阐明了EGR1-Zyxin信号通路参与缺血性卒中颅内静脉系统损伤机制，为未来优化再灌注治疗提供了新靶点。