Prolyl Hydroxylase Domain 2 Protein Suppresses Hypoxia-Induced Endothelial Cell Proliferation

Abstract

Prolyl hydroxylase domain 2 protein (PHD2) signals the degradation of hypoxia-inducible factor (HIF)-1α by hydroxylating specific prolyl residues located within oxygen-dependent degradation domains. As expected, endothelial cells (ECs) overexpressing PHD2 had reduced HIF-1α and vascular endothelial growth factor-A expression and failed to accelerate their proliferation in response to hypoxia. Surprisingly, although these cells displayed further reductions in HIF-1α and vascular endothelial growth factor-A expression when cultured under normoxia, there was no further reduction in EC proliferation. Thus, there seemed to be no consistent correlation between PHD2 hydroxylase–mediated suppression of HIF-1α expression and inhibition of EC growth. Indeed, overexpression of a mutant PHD2 lacking hydroxylase activity also greatly diminished EC response to hypoxia-induced increase in proliferation, in spite of the fact that hypoxia-induced HIF-1α accumulation was not affected by mutant PHD2. These data strongly sug...