RhoC maintains vascular homeostasis by regulating VEGF-induced signaling in endothelial cells.

ABSTRACT

Vasculogenesis and angiogenesis are controlled by vascular endothelial growth factor A (VEGF-A). Dysregulation of these physiological processes contributes to the pathologies of heart disease, cancer and stroke. Rho GTPase proteins play an integral role in VEGF-mediated formation and maintenance of blood vessels. The regulatory functions of RhoA and RhoB in vasculogenesis and angiogenesis are well defined, whereas the purpose of RhoC remains poorly understood. Here, we describe how RhoC promotes vascular homeostasis by modulating endothelial cell migration, proliferation and permeability. RhoC stimulates proliferation of human umbilical vein endothelial cells (HUVECs) by stabilizing nuclear ß-catenin, which promotes transcription of cyclin D1 and subsequently drives cell cycle progression. RhoC negatively regulates endothelial cell migration through MAPKs and downstream MLC2 signaling, and decreases vascular permeability through downregulation of the phospholipase Cγ (PLCγ)-Ca(2+)-eNOS cascade in HUVECs. Using a VEGF-inducible zebrafish (Danio rerio) model, we observed significantly increased vascular permeability in RhoC morpholino (MO)-injected zebrafish compared with control MO-injected zebrafish. Taken together, our findings suggest that RhoC is a key regulator of vascular homeostasis in endothelial cells.