Dynamic loss of lipid asymmetry through the activation of TMEM16 Ca2+-activated lipid scramblases (CaPLSases) has been increasingly recognized as an essential membrane event in a wide range of physiological and pathological processes, including blood coagulation, microparticle release, bone development, pain sensation, cell-cell fusion, and viral infection. Despite the recent implications of TMEM16F CaPLSase in vascular development and endothelial cell-mediated coagulation, its signaling role in endothelial biology remains to be established. Here, we show that endothelial TMEM16F regulates in vitro and in vivo angiogenesis through intracellular signaling. Developmental retinal angiogenesis is significantly impaired in TMEM16F deficient mice, as evidenced by fewer vascular loops and larger loop areas. Consistent with our in vivo observation, TMEM16F siRNA knockdown in human umbilical vein endothelial cells compromises angiogenesis in vitro. We further discovered that TMEM16F knockdown enhances VE-cadherin phosphorylation and reduces its expression. Moreover, TMEM16F knockdown also promotes Src kinase phosphorylation at tyrosine 416, which may be responsible for downregulating VE-cadherin expression. Our study thus uncovers a new biological function of TMEM16F in angiogenesis and provides a potential mechanism for how the CaPLSase regulates angiogenesis through intracellular signaling.
Keywords: CaPLSase; TMEM16F; angiogenesis; endothelial cells; scramblase.