NERF2, a member of the ets family of transcription factors, is increased in response to hypoxia and angiopoietin-1: A potential mechanism for Tie2 regulation during hypoxia

Vascular endothelial growth factor (VEGF) and angiopoietins regulate endothelial cell survival and migration and are essential for angiogenesis. Considerable progress has been made towards understanding hypoxia-mediated regulation of VEGF and its receptors. In contrast, little is known about the regulation of angiopoietins and their receptors in hypoxic cells. Using RT-PCR, RNAase protection assay, and Western blotting, we found that Tie1 and Tie2 mRNA and protein levels increased in response to hypoxia in human umbilical vein endothelial cells. Previously, we have shown that NERF2, a member of Ets family of transcription factors that is specifically expressed in endothelial cells, binds to the promoter region of Tie2 and transactivates Tie2 expression. In this study, we show that expression of NERF2 was increased under hypoxia and that this increase temporally correlated with the increase in Tie2 expression. Hypoxia-induced expression of NERF2 and Tie2 was blocked by angiopoietin-2, a competitive inhibitor of angiopoietin-1, and by recombinant soluble extracellular domain of Tie2 but not by VEGF-neutralizing antibodies. In addition, angiopoietin-1 directly induced expression of NERF2 in quiescent cells, These novel findings suggest that angiopoietin-1 regulates expression of NERF2 and its own receptor in hypoxic cells.