YAP1/TEAD1 upregulate platelet-derived growth factor receptor beta to promote vascular smooth muscle cell proliferation and neointima formation

J Mol Cell Cardiol. 2021 Jul:156:20-32. doi: 10.1016/j.yjmcc.2021.03.005. Epub 2021 Mar 19.

Abstract

We have previously demonstrated that the transcription co-factor yes-associated protein 1 (YAP1) promotes vascular smooth muscle cell (VSMC) de-differentiation. Yet, the role and underlying mechanisms of YAP1 in neointima formation in vivo remain unclear. The goal of this study was to investigate the role of VSMC-expressed YAP1 in vascular injury-induced VSMC proliferation and delineate the mechanisms underlying its action. Experiments employing gain- or loss-of-function of YAP1 demonstrated that YAP1 promotes human VSMC proliferation. Mechanistically, we identified platelet-derived growth factor receptor beta (PDGFRB) as a novel YAP1 target gene that confers the YAP1-dependent hyper-proliferative effects in VSMCs. Furthermore, we identified TEA domain transcription factor 1 (TEAD1) as a key transcription factor that mediates YAP1-dependent PDGFRβ expression. ChIP assays demonstrated that TEAD1 is enriched at a PDGFRB gene enhancer. Luciferase reporter assays further demonstrated that YAP1 and TEAD1 co-operatively activate the PDGFRB enhancer. Consistent with these observations, we found that YAP1 expression is upregulated after arterial injury and correlates with PDGFRβ expression and VSMC proliferation in vivo. Using a novel inducible SM-specific Yap1 knockout mouse model, we found that the specific deletion of Yap1 in adult VSMCs is sufficient to attenuate arterial injury-induced neointima formation, largely due to inhibited PDGFRβ expression and VSMC proliferation. Our study unravels a novel mechanism by which YAP1/TEAD1 promote VSMC proliferation via transcriptional induction of PDGFRβ, thereby enhancing PDGF-BB downstream signaling and promoting neointima formation.

Keywords: Gene expression and regulation; Genetically altered and transgenic models; Restenosis; Smooth muscle proliferation and differentiation; Vascular biology.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Becaplermin / metabolism
  • Cell Proliferation
  • Enhancer Elements, Genetic
  • Female
  • Gene Expression Regulation*
  • Mice
  • Models, Biological
  • Muscle, Smooth, Vascular / metabolism*
  • Myocytes, Smooth Muscle / metabolism*
  • Neointima / metabolism*
  • Promoter Regions, Genetic
  • Protein Binding
  • Receptor, Platelet-Derived Growth Factor beta / genetics*
  • Receptor, Platelet-Derived Growth Factor beta / metabolism
  • Signal Transduction
  • TEA Domain Transcription Factors / genetics*
  • TEA Domain Transcription Factors / metabolism
  • Transcriptional Activation
  • YAP-Signaling Proteins / genetics*
  • YAP-Signaling Proteins / metabolism

Substances

  • TEA Domain Transcription Factors
  • Tead1 protein, mouse
  • YAP-Signaling Proteins
  • Yap1 protein, mouse
  • Becaplermin
  • Receptor, Platelet-Derived Growth Factor beta