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

Yong Wang, Guoqing Hu, Fang Liu, Xiaobo Wang, Mingfu Wu, John J. Schwarz, Jiliang Zhou

Research output: Contribution to journalArticle

42 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)957-965
Number of pages9
JournalCirculation research
Volume114
Issue number6
DOIs
StatePublished - Mar 14 2014

Fingerprint

Vascular Smooth Muscle
Smooth Muscle Myocytes
G-Protein-Coupled Receptors
Proteins
Cardiac Myocytes
Cell Proliferation
Cell Cycle
Mouse Yap protein
Double Outlet Right Ventricle
cdc Genes
Cell Cycle Resting Phase
Subclavian Artery
Histone Deacetylases
Muscle Development
Ventricular Heart Septal Defects
G1 Phase
Cell Cycle Checkpoints
Epigenomics
Knockout Mice
Transgenic Mice

Keywords

  • abnormalities
  • blood supply
  • developmental biology
  • muscle
  • myocardium
  • smooth
  • transcription factors
  • vascular

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Deletion of yes-associated protein (YAP) specifically in cardiac and vascular smooth muscle cells reveals a crucial role for YAP in mouse cardiovascular development. / Wang, Yong; Hu, Guoqing; Liu, Fang; Wang, Xiaobo; Wu, Mingfu; Schwarz, John J.; Zhou, Jiliang.

In: Circulation research, Vol. 114, No. 6, 14.03.2014, p. 957-965.

Research output: Contribution to journalArticle

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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.",
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AU - Wang, Yong

AU - Hu, Guoqing

AU - Liu, Fang

AU - Wang, Xiaobo

AU - Wu, Mingfu

AU - Schwarz, John J.

AU - Zhou, Jiliang

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