Abstract 290: The Transcription Factor Tead1 is Critical for Vascular Development in Mouse by Promoting Differentiation of Vascular Smooth Muscle Cells

Abstract

Background: Our previous study has shown that the Hippo signaling effector YAP plays a crucial role in the phenotypic modulation of vascular smooth muscle cells (VSMCs) in response to arterial injury and cardiovascular development in mice. However, the role of TEAD1, a co-factor of YAP in VSMC development is unknown. Objective: The goal of this study to investigate the functional role of TEAD1 in cardiovascular development in mice. Methods and Results: TEAD1 was specifically ablated in cardiomyocytes and VSMCs by crossing TEAD1 flox mice with SM22alpha-Cre transgenic mice. Cardiac/VSMC-specific deletion of TEAD1 led to embryonic lethality by E14.5 in mice due to cardiovascular defects including severe hypoplastic cardiovascular wall, resulting from impaired cardiac/VSMC proliferation. Whole transcriptomic analysis revealed deletion of TEAD1 in mouse cardiomyocytes and VSMCs significantly down-regulated expression of cardiac/VSMC differentiation genes and key transcription factors including myocardin and pitx2c that are critical for cardiovascular development. In vitro studies demonstrated that myocardin and pitx2c rescued TEAD1-defiency induced defects of VSMC differentiation. Furthermore, we identified pitx2c was a direct transcriptional target of TEAD1 and pitx2c synergistically promoted VSMC differentiation with myocardin. Conclusions: This study revealed a critical role of TEAD1 in cardiovascular development by promoting VSMC proliferation and differentiation and provided novel insights into the regulatory mechanisms for smooth muscle development.