TM4SF1 mediates YAP/TAZ regulation of coronary artery formation

Abstract

Abstract Although the role of YAP/TAZ in mediating VEGF-driven angiogenesis is well established, their downstream effectors in coronary artery development remain elusive. In this study, we identify TM4SF1 as a novel downstream target of YAP/TAZ in coronary endothelial cells. Conditional deletion of YAP/TAZ in the endocardial lineage resulted in embryonic lethality due to congenital heart defects, including ventricular noncompaction. Mutant embryos exhibited severe coronary vessel defects, including the absence of major arteries. Loss of YAP/TAZ significantly inhibited endothelial cell proliferation and coronary angiogenesis. Transcriptomic profiling revealed that YAP/TAZ deficiency downregulated the expression of TM4SF1, a known regulator of angiogenesis, in the endocardium and coronary endothelium. Consistently, YAP/TAZ were required for VEGF-induced upregulation of TM4SF1 in endothelial cells. Moreover, YAP/TAZ-mediated upregulation of TM4SF1 was essential for VEGF-driven angiogenesis in HUVECs. Together, these findings indicate that TM4SF1 functions downstream of YAP/TAZ to regulate endothelial angiogenic processes, suggesting a potential role for TM4SF1 in coronary artery development.