The Induction of Yes-Associated Protein Expression After Arterial Injury Is Crucial for Smooth Muscle Phenotypic Modulation and Neointima Formation

• DOI: 10.1161/atvbaha.112.254730
• Publication Date: 2012-08-25T00:15:29Z
• Authors: Xiaobo Wang; Guoqing Hu; Xiangwei Gao; Yong Wang; Wei Zhang; Erin Yund Harmon; Xu Zhi; Zhengping Xu; Michelle R. Lennartz; Margarida Barroso; Mohamed Trebak; Ceshi Chen; Jiliang Zhou
• Keywords: Male; 0301 basic medicine; Genotype; Myocytes, Smooth Muscle; Cell Cycle Proteins; Muscle, Smooth, Vascular; Mice, Inbred C57BL; Disease Models, Animal; Mice; 03 medical and health sciences; Carotid Arteries; Gene Expression Regulation; Cell Movement; Gene Knockdown Techniques; Neointima; Animals; Apoptosis Regulatory Proteins; Carotid Artery Injuries; Aorta; Cells, Cultured; Adaptor Proteins, Signal Transducing; Cell Proliferation

Objective— 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 yes-associated protein (YAP) in SM phenotypic modulation in vitro and in vivo.

Methods and Results— In vitro 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. Overexpression of YAP promotes SMC migration and proliferation while attenuating SM contractile gene expression. Conversely, knocking down endogenous YAP in SMCs upregulates SM 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 SM phenotypic switch and neointima formation.

Conclusion— YAP plays a novel integrative role in SM phenotypic modulation by inhibiting SM-specific gene expression while promoting SM proliferation and migration in vitro and in vivo. Blocking the induction of YAP would be a potential therapeutic approach for ameliorating vascular occlusive diseases.