细胞外基质介导的YAP蛋白活化在血管平滑肌表型转化以及动脉粥样硬化过程中的作用与机制研究

Atherosclerosis is a common disease in human populations and is highly dangerous. Alterations in extracellular matrix components are the key step in the development of atherosclerosis. Pathological extracellular matrix (fibronectin and type I collagen) can promote vascular smooth muscle cell (VSMC) switch from contractile to synthetic type and exacerbate atherosclerosis. YAP is an important co-transcription factor in the regulation of VSMC proliferation and apoptosis. However, the role and mechanism of YAP in extracellular matrix-mediated smooth muscle cell phenotypic switch and atherosclerosis is still unclear. Our preliminary data indicates that YAP is highly expressed in mice atherosclerotic plaque, and pathological extracellular matrix can upregulate YAP expression and mediate smooth muscle cell phenotypic switch. Thus we hypothesize that different extracellular matrix mediates VSMC phenotypic switch through the regulation of YAP expression, and thus further affect the development and progression of atherosclerosis. This project will use smooth muscle cell specific YAP transgenic mice and atherosclerotic model to study the general effect and meanwhile use cultured primary smooth muscle cell to study the underlying mechanisms, which may help to elucidate the mechanism of atherosclerosis.

动脉粥样硬化疾病在人群中发病率高，危害极大。血管细胞外基质成分的改变是动脉粥样硬化发病的关键步骤，病理性细胞外基质（纤维连接蛋白及I型胶原）可以促进血管平滑肌表型由收缩型转变为分泌型并进一步加重动脉粥样硬化的发展。共转录因子YAP蛋白是调控血管平滑肌增殖和凋亡的重要因子，但其在细胞外基质介导的平滑肌表型转化以及动脉粥样硬化发展过程中的作用与机制尚不清楚。本课题组预实验结果提示动脉粥样硬化小鼠斑块处YAP高表达，同时病理性细胞外基质可以上调YAP表达并介导平滑肌表型转化。据此我们推测不同细胞外基质可以通过调控YAP表达介导平滑肌表型转化，进而影响动脉粥样硬化的发生与发展。本课题拟用YAP平滑肌特异性过表达小鼠及动脉粥样硬化模型进行整体研究，同时使用原代平滑肌细胞培养等手段进行机制研究，以期阐明动脉粥样硬化的发生机制。

血管新生是一项受多条信号通路共同调控的复杂生理过程，在动脉粥样硬化疾病等诸多生理以及病理生理过程中发挥重要调控作用。Hippo-YAP通路在诸多生理过程中起到诸如调控细胞增殖等作用，但调控血管新生的机制尚不清楚，本研究通过内皮细胞实验证实了YAP对于内皮细胞迁移和增殖功能的影响，分子生物学实验上证实了其与转录因子STAT3相互作用并进一步导致IL6介导的STAT3在细胞核中滞留延长，功能实验上我们使用内皮细胞特异性过表达YAP蛋白的小鼠，证实了其在出生后视网膜血管，肿瘤血管等血管新生过程中的作用。研究揭示了YAP蛋白的新的作用以及新的作用方式，拓展了领域内对Hippo-YAP信号通路的认识。我们的研究论文发表在Circ Res上，同时受邀撰写YAP在心血管系统中的作用的综述（BJP）一篇。整体上，发表基金标注论文7篇，其中5篇为第一作者或责任作者；研究成果申请国家发明专利一项。