脑血管疾病是威胁人类健康的重大疾病，血流动力学对于维持血脑屏障（BBB）的结构和功能具有决定性作用。然而，在正常生理、缺血低灌注和搭桥术后高灌注下，脑血管中不同强度的剪切力对BBB的保护、损伤和破坏机制尚未明确。力学敏感蛋白YAP的活性与细胞间接触抑制和紧密连接密切相关。我们前期结果表明：生理水平的剪切力上调YAP的表达；而高剪切力诱导rBMECs通透性增加，YAP表达显著降低。由此推测：剪切力通过YAP通路调控BBB结构和功能。本项目拟通过新型流动腔系统及脑缺血大鼠模型，探讨流体剪切力对rBMECs紧密连接和通透性的影响，通过解析“Integrin-YAP-Rho GTPases-F-actin”信号轴上关键蛋白表达和分布的时序规律，以及YAP入核活化机理，明确在生理和病理条件下，YAP参与流体剪切力调控BBB的力学生物学机制。研究结果对脑血管介入材料的设计具有重要的指导意义。

Cerebrovascular diseases are one of the most serious diseases that threaten human health. The haemodynamics play a central role in maintaining the structure and function of blood-brain barrier (BBB) in cerebral vessels. However, under the condition of normal physiology, ischemia hypoperfusion and hypertransfusion, the mechanisms that how fluid shear stress (FSS) protect, damage and destruct BBB are still unclear. The activation of YAP is closely related to the intercellular contact inhibition and tight junction. Our previous results indicated that, under the physiological condition, FSS upregulated the expression of YAP, while high FSS could induce the cytoskeleton rearrangement of rBMECs, increased the intercellular permeability, and downregulate the YAP level. Accordingly, we speculated that fluid shear stress regulated the structure and function by YAP pathway. Using novel flow chamber system and cerebral ischemia rat model, this project aims to examine the effects of different intensity of FSS on the structure and function of cerebrovascular endothelial cells and BBB. Additionally, the time-dependent expression and distribution of key proteins in the “Integrin/YAP/Rho GTPases/F-actin” signal pathway will be studied, and the mechanism of activated YAP in nucleus will be analyzed to further explore the mechanobiologic mechanisms that YAP induced FSS regulating BBB. The finding of this project would provide the suggestions and guides for the design and improvement of cerebrovascular interventional implants.