Endothelial HIF-2? regulates murine pathological angiogenesis and revascularization processes.

ABSTRACT: Localized tissue hypoxia is a consequence of vascular compromise or rapid cellular proliferation and is a potent inducer of compensatory angiogenesis. The oxygen-responsive transcriptional regulator hypoxia-inducible factor 2? (HIF-2?) is highly expressed in vascular ECs and, along with HIF-1?, activates expression of target genes whose products modulate vascular functions and angiogenesis. However, the mechanisms by which HIF-2? regulates EC function and tissue perfusion under physiological and pathological conditions are poorly understood. Using mice in which Hif2a was specifically deleted in ECs, we demonstrate here that HIF-2? expression is required for angiogenic responses during hindlimb ischemia and for the growth of autochthonous skin tumors. EC-specific Hif2a deletion resulted in increased vessel formation in both models; however, these vessels failed to undergo proper arteriogenesis, resulting in poor perfusion. Analysis of cultured HIF-2?-deficient ECs revealed cell-autonomous increases in migration, invasion, and morphogenetic activity, which correlated with HIF-2?-dependent expression of specific angiogenic factors, including delta-like ligand 4 (Dll4), a Notch ligand, and angiopoietin 2. By stimulating Dll4 signaling in cultured ECs or restoring Dll4 expression in ischemic muscle tissue, we rescued most of the HIF-2?-dependent EC phenotypes in vitro and in vivo, emphasizing the critical role of Dll4/Notch signaling as a downstream target of HIF-2? in ECs. These results indicate that HIF-1? and HIF-2? fulfill complementary, but largely nonoverlapping, essential functions in pathophysiological angiogenesis.

SUBMITTER: Skuli N 

PROVIDER: S-EPMC3314446 | biostudies-literature | 2012 Apr

REPOSITORIES: biostudies-literature