The induction of yes-associated protein expression after arterial injury is crucial for smooth muscle phenotypic modulation and neointima formation.
The induction of yes-associated protein expression after arterial injury is crucial for smooth muscle phenotypic modulation and neointima formation.
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DOI：
10.1161/atvbaha.112.254730
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发表时间：
2012-11
期刊：
影响因子：
--
通讯作者：
Zhou J
中科院分区：
文献类型：
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作者：
Wang X;Hu G;Gao X;Wang Y;Zhang W;Harmon EY;Zhi X;Xu Z;Lennartz MR;Barroso M;Trebak M;Chen C;Zhou J
血管平滑肌细胞（SMC）的异常增殖和迁移是血管损伤后新生内膜形成过程中的关键事件。本研究的目的是研究一种有效的癌基因雅普在平滑肌表型调节中的功能作用。在体外细胞培养和体内小鼠和大鼠动脉损伤模型中，雅普表达被显著诱导，并且与血管SMC合成表型相关。过表达雅普促进SMC迁移和增殖，同时减弱平滑肌收缩基因表达。相反，敲低SMC中的内源性雅普上调平滑肌基因表达，但减弱SMC增殖和迁移。与此一致，在大鼠颈动脉球囊损伤模型中敲低雅普表达和在小鼠颈动脉结扎损伤后血管SMC中特异性地基因缺失雅普可减弱损伤诱导的平滑肌表型转换和新生内膜形成。雅普通过抑制平滑肌特异性基因表达，同时促进平滑肌增殖和迁移，在体外和体内平滑肌表型调节中发挥新的整合作用。阻断雅普的诱导将是改善血管闭塞性疾病的潜在治疗方法。
Abnormal proliferation and migration of vascular smooth muscle cells (SMCs) are the key events in the progression of neointima formation in response to vascular injury. The goal of this study is to investigate the functional role of a potent oncogene YAP in smooth muscle phenotypic modulation in vitro and in vivo. In vitro in cell culture and in vivo in both mouse and rat arterial injury models YAP expression is significantly induced and correlated with the vascular SMC synthetic phenotype. Over-expression of YAP promotes SMC migration and proliferation while attenuating smooth muscle contractile gene expression. Conversely, knocking-down endogenous YAP in SMCs up-regulates smooth muscle gene expression but attenuates SMC proliferation and migration. Consistent with this, knocking-down YAP expression in a rat carotid balloon injury model and genetic deletion of YAP specifically in vascular SMCs in mouse after carotid artery ligation injury attenuates injury-induced smooth muscle phenotypic switch and neointima formation. YAP plays a novel integrative role in smooth muscle phenotypic modulation by inhibiting smooth muscle-specific gene expression while promoting smooth muscle proliferation and migration in vitro and in vivo. Blocking the induction of YAP would be a potential therapeutic approach for ameliorating vascular occlusive diseases.