Abstract 109: Yes-associated Protein Upregulates Platelet Derived Growth Factor Receptor Beta to Promote Vascular Smooth Muscle Cell Proliferation and Neointima Formation

Abstract

Rationale: Previously, we demonstrated that YAP (Yes-associated Protein), a Hippo signaling effector, promotes vascular smooth muscle cell (VSMC) proliferation. However, the role and underlying mechanisms of SM-expressed YAP in neointima formation remain unknown. Objective: To assess the role of SM-expressed YAP in vascular injury-induced smooth muscle cell proliferation and delineate its underlying mechanism. Methods and Results: We found that YAP expression is enhanced in mouse carotid artery after ligation injury and correlates with upregulation of Platelet-derived Growth Factor Receptor Beta (PDGFRβ) in vivo. Mechanistically, gain- and loss-of-function of YAP studies demonstrated that YAP transcriptionally induces PDGFRβ expression and enhances PDGF-BB-elicited pro-mitogenic signaling, leading to enhanced VSMC proliferation. Importantly, depletion of PDGFRβ abolished YAP-mediated VSMC proliferation. Furthermore, we found that over-expression of TEAD1, a transcription factor that mediates YAP binding to DNA, mimics YAP function in inducing PDGFRβ expression. Conversely, depletion of TEAD1 abolished YAP-dependent PDGFRβ expression. ChIP assays further demonstrated that TEAD1 protein is enriched at multiple enhancer sequences in PDGFRβ gene locus. Finally, using an inducible smooth muscle-specific YAP knockout mouse model, we found that specific deletion of YAP in VSMCs is sufficient to attenuate arterial injury-induced neointima formation and VSMC proliferation, resulting from attenuated PDGFRβ expression. Conclusions: Our study unravels a novel mechanism by which YAP/TEAD1 promote VSMC proliferation via transcriptional induction of PDGFRβ expression, thereby enhancing neointima formation.