Deletion of yes-associated protein (YAP) specifically in cardiac and vascular smooth muscle cells reveals a crucial role for YAP in mouse cardiovascular development.
BACKGROUND
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.


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 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.
From the Department of Pharmacology and Toxicology, Medical College of Georgia, Georgia Regents University, Augusta (Y.W., G.H., F.L., J.Z.); and Center for Cardiovascular Sciences, Albany Medical College, NY (X.W., M.W., J.J.S.).
Yong
Y
Wang
Guoqing
G
Hu
Fang
F
Liu
Xiaobo
X
Wang
Mingfu
M
Wu
John J
JJ
Schwarz
Jiliang
J
Zhou
D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000783:Aneurysm / Q000235:genetics; D000818:Animals; D016122:Brachiocephalic Trunk / Q000002:abnormalities; D018376:Cardiovascular Abnormalities / Q000196:embryology / Q000235:genetics*; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D002455:Cell Division; D002478:Cells, Cultured; D004310:Double Outlet Right Ventricle / Q000196:embryology / Q000235:genetics; D005318:Fetal Heart / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental / Q000235:genetics / Q000502:physiology*; D005804:Genes, Lethal; D018816:Genes, cdc; D006345:Heart Septal Defects, Ventricular / Q000196:embryology / Q000235:genetics; D006655:Histone Deacetylases / Q000378:metabolism / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009131:Muscle, Smooth, Vascular / Q000473:pathology; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000166:cytology* / Q000473:pathology; D010750:Phosphoproteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D013348:Subclavian Artery / Q000002:abnormalities; D000091102:YAP-Signaling Proteins
D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; C115270:G2A receptor; D010750:Phosphoproteins; D034741:RNA, Small Interfering; D043562:Receptors, G-Protein-Coupled; D000091102:YAP-Signaling Proteins; C486223:Yap1 protein, mouse; C559944:HDAC4 protein, rat; C498618:Hdac5 protein, mouse; D006655:Histone Deacetylases
abnormalities; blood supply; developmental biology; muscle, smooth; muscle, smooth, vascular; myocardium; transcription factors