The small GTPases RhoA and RhoB are involved in vasculogenesis and angiogenesis; however, the role of another Rho family member, RhoC, in these processes has – despite its high sequence similarity to RhoA and RhoB – only been investigated in a few studies. In this issue (p. ), Debabrata Mukhopadhyay and colleagues used human umbilical vein endothelial cells (HUVECs) to show that RhoC maintains endothelial cell homeostasis. They found that treatment of HUVECs with vascular endothelial growth factor (VEGF) activates RhoC through the VEGF receptor 2 (VEGFR-2). Upon VEGF stimulation, RhoC reduced the migration of HUVECs and human brain microvascular endothelial cells, and also increased proliferation of HUVECs and lymphatic microvascular endothelial cells. The latter was owing to RhoC-mediated stabilisation of β-catenin, which, in turn, upregulated cyclin D1 and promoted cell cycle progression. Furthermore, the authors were able to show that RhoC inhibited cell migration by preventing activation of the ERK1/2, p38 family and JNK family signalling pathways and the subsequent downstream phosphorylation of myosin light chain 2 (MLC2). Finally, RhoC negatively regulated cell permeability through inhibition of VEGF-induced phosphorylation of PLCγ and downstream activation of eNOS, as well as intracellular Ca2+ release. The authors also confirmed these findings in a zebrafish model of vascular permeability. Thus, this study presents strong evidence that RhoC modulates the effects of VEGF on migration, proliferation and permeability, thereby acting as a main regulator of endothelial cell homeostasis.
