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. 2014 Mar 14;114(6):957-65. doi: 10.1161/CIRCRESAHA.114.303411. Epub 2014 Jan 29.

Abstract

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 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.

Keywords: abnormalities; blood supply; developmental biology; muscle, smooth; muscle, smooth, vascular; myocardium; transcription factors.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adaptor Proteins, Signal Transducing / deficiency
  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / physiology*
  • Aneurysm / genetics
  • Animals
  • Brachiocephalic Trunk / abnormalities
  • Cardiovascular Abnormalities / embryology
  • Cardiovascular Abnormalities / genetics*
  • Cell Cycle Proteins / antagonists & inhibitors
  • Cell Cycle Proteins / biosynthesis
  • Cell Cycle Proteins / genetics
  • Cell Division
  • Cells, Cultured
  • Double Outlet Right Ventricle / embryology
  • Double Outlet Right Ventricle / genetics
  • Fetal Heart / physiology*
  • Gene Expression Regulation, Developmental / genetics
  • Gene Expression Regulation, Developmental / physiology*
  • Genes, Lethal
  • Genes, cdc
  • Heart Septal Defects, Ventricular / embryology
  • Heart Septal Defects, Ventricular / genetics
  • Histone Deacetylases / metabolism
  • Histone Deacetylases / physiology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Muscle, Smooth, Vascular / pathology
  • Myocytes, Cardiac / cytology*
  • Myocytes, Cardiac / pathology
  • Myocytes, Smooth Muscle / cytology*
  • Myocytes, Smooth Muscle / pathology
  • Phosphoproteins / deficiency
  • Phosphoproteins / genetics
  • Phosphoproteins / physiology*
  • Promoter Regions, Genetic
  • RNA Interference
  • RNA, Small Interfering / pharmacology
  • Rats
  • Receptors, G-Protein-Coupled / antagonists & inhibitors
  • Receptors, G-Protein-Coupled / biosynthesis
  • Receptors, G-Protein-Coupled / genetics
  • Subclavian Artery / abnormalities

Substances

  • Adaptor Proteins, Signal Transducing
  • Cell Cycle Proteins
  • G2A receptor
  • Phosphoproteins
  • RNA, Small Interfering
  • Receptors, G-Protein-Coupled
  • Yap1 protein, mouse
  • HDAC4 protein, rat
  • Hdac5 protein, mouse
  • Histone Deacetylases