YAP1/TEAD1 upregulate platelet-derived growth factor receptor beta to promote vascular smooth muscle cell proliferation and neointima formation. (July 2021)

• Record Type: Journal Article
• Authors: Osman, Islam; Dong, Kunzhe; Kang, Xiuhua; Yu, Luyi; Xu, Fei; Ahmed, Abu Shufian Ishtiaq; He, Xiangqin; Shen, Jian; Hu, Guoqing; Zhang, Wei; Zhou, Jiliang
• Is Part Of: Journal of molecular and cellular cardiology. Volume 156(2021)
• Page Start: 20
• Page End: 32
• Publication Date: 2021-07
• Subjects: Smooth muscle proliferation and differentiation -- Restenosis -- Vascular biology -- Gene expression and regulation -- Genetically altered and transgenic models; Cardiology -- Periodicals; Heart Diseases -- Periodicals; Molecular Biology -- Periodicals; Cardiologie -- Périodiques; Cardiology; Electronic journals; Periodicals; 616.12
• DOI: 10.1016/j.yjmcc.2021.03.005
• Languages: English
• ISSNs: 0022-2828

Abstract

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. Graphical abstract: Unlabelled Image Highlights: Vascular injury-induces YAP1 expression to promote the expression of TEAD1. YAP1 forms a transcriptional complex with TEAD1 to activate PDGFRβ expression. Upregulated PDGFRβ expression promotes PDGF-BB-mediated pro-mitogenic signaling. PDGF-BB signaling enhances VSMC proliferation and injury-induced neointima formation. Blocking YAP1/TEAD1-PDGFRβ axis is a promising approach to ameliorate restenosis.