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Endothelial HIF-2 α regulates murine pathological angiogenesis and revascularization processes
- Source :
- Journal of Clinical Investigation. April 1, 2012, Vol. 122 Issue 4, p1427, 17 p.
- Publication Year :
- 2012
-
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 α (HIF-2 α) is highly expressed in vascular ECs and, along with HIF-1 α, activates expression of target genes whose products modulate vascular functions and angiogenesis. However, the mechanisms by which HIF-2 α 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 α 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 α - deficient ECs revealed cell-autonomous increases in migration, invasion, and morphogenetic activity, which correlated with HIF-2 α -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 α -dependent EC phenotypes in vitro and in vivo, emphasizing the critical role of Dll4/Notch signaling as a downstream target of HIF-2 α in ECs. These results indicate that HIF-1 α and HIF-2 α fulfill complementary, but largely nonoverlapping, essential functions in pathophysiological angiogenesis.<br />Introduction The therapeutic manipulation of angiogenesis holds great promise for treating diverse pathological conditions, including cancer, macular degeneration, atherosclerosis, and peripheral arterial disease (PAD) (1), (2). However, the ability to [...]
Details
- Language :
- English
- ISSN :
- 00219738
- Volume :
- 122
- Issue :
- 4
- Database :
- Gale General OneFile
- Journal :
- Journal of Clinical Investigation
- Publication Type :
- Academic Journal
- Accession number :
- edsgcl.286559297
- Full Text :
- https://doi.org/10.1172/JCI57322