机械力信号通路Piezo1-bestrophin3下调促进主动脉夹层发生及机制

血液动力学是主动脉夹层（AD）发生的关键危险因素，但机理不清。预实验结果发现AD患者血管Piezo1机械力敏感通道表达降低，敲除平滑肌Piezo1导致血管结构异常，诱发AD形成。芯片分析发现Piezo1敲除导致bestrophin3表达降低，敲除平滑肌bestrophin3同样诱发AD。进一步发现，bestrophin3 和MEKK2/3激酶相结合，bestrophin3敲除上调MEKK2/3活性。据此我们提出AD发生新机制：即Piezo1下调导致bestrophin3表达降低，进而激活MEKK2/3信号通路。本项目旨在：证实Piezo1-bestrophin3-MEKK2/3是新的机械力信号通路，阐明该信号通路失衡在AD发生中的作用并揭示其机理。工作将从管壁机械力敏感性降低导致管壁细胞适应性重塑失衡角度揭示AD发生新机制，为明确Piezo1机械力信号通路是防治AD有效新靶点提供理论依据。

Hemodynamics is an important risk factor for development of aortic dissection (AD), but its mechanisms are not clear. Our preliminary data showed the expression of mechanical-sensitive Piezo1 channel is decreased in AD patients. Knockout of Piezo1 in vascular smooth muscle cells induces abnormal structure of aorta and spontaneous AD formation. Gene chip array demonstrated Piezo1 knockout induces decreased expression of bestrophin3 in vascular smooth muscle cells. Moreover, Knockout of bestrophin3 in smooth muscle cells also induces spontaneous AD formation. Furthermore, we observed the direct interaction between bestrophin3 and MEKK2/3, bestrophin3 knockout increases the phosphorylation of MEKK2/3. Our hypothesis is: Downregulation of Piezo1 could decrease the expression of bestrophin3, thus activates MEKK2/3 due to losing the inhibitory effects exerted by bestophin3, and finally leads to AD formation. The aim in present study is to clarify the critical role of the imbalance of Piezo1-bestrophin3-MEKK2/3 signaling pathway in AD development and to reveal its mechanisms. Our work will unveil the new mechanism of AD from the perspective of Piezo 1 mechanical-sensitive ion channel, and provide theoretical basis for clarifying whether this signaling pathway is an effective novel target for AD prevention and treatment.