Deletion of Yes-Associated Protein ( YAP) Specifically in Cardiac and Vascular Smooth Muscle Cells Reveals a Crucial Role for YAP in Mouse Cardiovascular Development

Rationale: Our previous study has shown that yes-associated protein (YAP) plays a crucial role in the phenotypic modulation of vascular smooth muscle cells (SMCs) in response to arterial injury. However, the role of YAP in vascular SMC development is unknown. Objective: The goal of this study was to investigate the functional role of YAP in cardiovascular development in mice and determine the mechanisms underlying YAP's actions. Methods and Results: YAP was deleted in cardiomyocytes and vascular SMCs by crossing YAP flox mice with SM22-Cre transgenic mice. Cardiac/SMC-specific deletion of YAP directed by SM22-Cre resulted in perinatal lethality in mice because of profound cardiac defects including hypoplastic myocardium, membranous ventricular septal defect, and double outlet right ventricle. The cardiac/SMC-specific YAP knockout mice also displayed severe vascular abnormalities including hypoplastic arterial wall, short/absent brachiocephalic artery, and retroesophageal right subclavian artery. Deletion of YAP in mouse vascular SMCs induced expression of a subset of cell cycle arrest genes including G-protein-coupled receptor 132 (Gpr132). Silencing Gpr132 promoted SMC proliferation, whereas overexpression of Gpr132 attenuated SMC growth by arresting cell cycle in G0/G1 phase, suggesting that ablation of YAP-induced impairment of SMC proliferation was mediated, at least in part, by induction of Gpr132 expression. Mechanistically, YAP recruited the epigenetic repressor histone deacetylase-4 to suppress Gpr132 gene expression via a muscle CAT element in the Gpr132 gene. Conclusions: YAP plays a critical role in cardiac/SMC proliferation during cardiovascular development by epigenetically regulating expression of a set of cell cycle suppressors.