TMEM30A deficiency in endothelial cells impairs cell proliferation and angiogenesis

Abstract

Phosphatidylserine (PS) asymmetry in the eukaryotic cell membrane is maintained by a group of proteins belonging to the P4-ATPase family, namely, PS flippases. The folding and transporting of P4-ATPases to their cellular destination requires a β-subunit member of the TMEM30 protein family. Loss of <i>Tmem30a</i> has been shown to cause multiple disease conditions. However, its roles in vascular development have not been elucidated. Here, we show that <i>TMEM30A</i> plays critical roles in retinal vascular angiogenesis, which is a fundamental process in vascular development. Our data indicate that knockdown of <i>TMEM30A</i> in primary human retinal endothelial cells led to reduced tube formation. In mice, endothelial cell (EC)-specific deletion of <i>Tmem30a</i> led to retarded retinal vascular development with a hyperpruned vascular network as well as blunted-end, aneurysm-like tip ECs with fewer filopodia at the vascular front and a reduced number of tip cells. Deletion of <i>Tmem30a</i> also impaired vessel barrier integrity. Mechanistically, deletion of <i>TMEM30A</i> caused reduced EC proliferation by inhibiting VEGF-induced signaling. Our findings reveal essential roles of <i>TMEM30A</i> in angiogenesis, providing a potential therapeutic target.