| First Author | Wang Y | Year | 2014 |
| Journal | Circ Res | Volume | 114 |
| Issue | 6 | Pages | 957-65 |
| PubMed ID | 24478334 | Mgi Jnum | J:221298 |
| Mgi Id | MGI:5638844 | Doi | 10.1161/CIRCRESAHA.114.303411 |
| Citation | Wang Y, et al. (2014) Deletion of yes-associated protein (YAP) specifically in cardiac and vascular smooth muscle cells reveals a crucial role for YAP in mouse cardiovascular development. Circ Res 114(6):957-65 |
| abstractText | 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 SM22alpha-Cre transgenic mice. Cardiac/SMC-specific deletion of YAP directed by SM22alpha-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. |
