PCDH7下调通过诱导血管平滑肌细胞表型转换促进主动脉夹层形成及机制研究

血管平滑肌细胞表型转换是动脉夹层（AD）的重要病理基础，但机理不清。我们利用多芯片联合分析发现原钙黏蛋白PCDH7在AD组织中表达显著下调。恢复其表达可有效抑制AD形成。进一步发现，血管平滑肌细胞PCDH7敲除上调Ras表达，激活Ras–MEK通路，从而抑制平滑肌细胞收缩型标志蛋白表达。由此，我们提出PCDH7–Ras–MEK是影响AD发生发展的关键因素，即：PCDH7表达下调导致Ras–MEK信号激活，诱导血管平滑肌细胞从收缩型向合成型转换，促进AD形成。在此基础上，本研究拟采用PCDH7平滑肌特异性敲除和高表达小鼠，制备AD模型，明确PCDH7对AD形成的作用，并从调控Ras表达及其下游Ras–MEK信号激活的角度揭示PCDH7调控AD形成的分子机制。该工作将从调控血管平滑肌细胞表型转换角度阐明钙黏蛋白在心血管系统中的新功能，且为评估PCDH7是否可作为防治AD的新靶点提供实验依据。

Vascular smooth muscle cell (VSMC) phenotypic transformation is one of the important contributors to arterial dissection (AD), but the mechanisms underpinning its pathogenesis have not been completely established. Integrating the published genomic data available in the Gene Expression Omnibus with AD samples from clinical and experimental samples, we discovered that PCDH7 expression is significantly decreased compared with normal samples. Restoration of PCHD7 attenuated AD formation in mouse model of angiotensin II-induced AD. We further evidenced that knockout of PCDH7 in VSMCs increased Ras expression and subsequently activated Ras–MEK signaling, leading to elevated VSMC differentiation marker genes expression. Thus, we suppose that PCDH7–Ras–MEK axis is critical for AD, suggesting PCDH7 downregulation results in Ras–MEK signaling activation and VSMC phenotype transformation, which promotes AD progression. The present study aims to investigate the effects of PCDH7 on AD and the underlying mechanism. This work will unveil the novel functional role of cadherins in cardiovascular system and provide convinced evidences that PCDH7 may be an important therapeutic target for the treatment of AD.