Deletion of 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 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 SM22α-Cre transgenic mice. Cardiac/SMC-specific deletion of YAP directed by SM22α Cre resulted in perinatal lethality in mice due to profound cardiac defects including hypoplastic myocardium, membranous ventricular septal defect, and double outlet right ventricle. The cardiac/SMC-specific YAP knock-out mice also displayed severe vascular abnormalities including hypoplastic arterial wall, short/absent brachiocephalic artery and retro-esophageal right subclavian artery. Deletion of YAP in mouse vascular SMCs induced expression of a subset of cell cycle arrest genes including Gpr132. Silencing Gpr132 promoted SMC proliferation while over-expression of Gpr132 attenuated SMC growth by arresting cell cycle in G0/G1 phase, suggesting 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, HDAC4 to suppress Gpr132 gene expression via an MCAT element in the Gpr132 gene.
Conclusions: YAP plays a critical role in cardiac/smooth muscle cell proliferation during cardiovascular development by epigenetically regulating expression of a set of cell cycle suppressors.
- smooth muscle cell
- transcription factors
- vascular smooth muscle
- vascular biology
- developmental biology
- Received January 7, 2014.
- Revision received January 27, 2014.
- Accepted January 29, 2014.