title: Endothelial HIF-2α 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 2α (HIF-2α) is highly expressed in vascular ECs and, along with HIF-1α, activates expression of target genes whose products modulate vascular functions and angiogenesis. However, the mechanisms by which HIF-2α 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-2α 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-2α-deficient ECs revealed cell-autonomous increases in migration, invasion, and morphogenetic activity, which correlated with HIF-2α-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-2α-dependent EC phenotypes in vitro and in vivo, emphasizing the critical role of Dll4/Notch signaling as a downstream target of HIF-2α in ECs. These results indicate that HIF-1α and HIF-2α fulfill complementary, but largely nonoverlapping, essential functions in pathophysiological angiogenesis.
authors.affiliation: Howard Hughes Medical Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6160, USA.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Skuli
authors.forename: Amar J
authors.initials: AJ
authors.lastname: Majmundar
authors.forename: Bryan L
authors.initials: BL
authors.lastname: Krock
authors.forename: Rickson C
authors.initials: RC
authors.lastname: Mesquita
authors.forename: Lijoy K
authors.initials: LK
authors.lastname: Mathew
authors.forename: Zachary L
authors.initials: ZL
authors.lastname: Quinn
authors.forename: Anja
authors.initials: A
authors.lastname: Runge
authors.forename: Liping
authors.initials: L
authors.lastname: Liu
authors.forename: Meeri N
authors.initials: MN
authors.lastname: Kim
authors.forename: Jiaming
authors.initials: J
authors.lastname: Liang
authors.forename: Steven
authors.initials: S
authors.lastname: Schenkel
authors.forename: Arjun G
authors.initials: AG
authors.lastname: Yodh
authors.forename: Brian
authors.initials: B
authors.lastname: Keith
authors.forename: M Celeste
authors.initials: MC
authors.lastname: Simon
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D042702:Angiopoietin-2 / Q000235:genetics / Q000502:physiology; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D002135:Calcium-Binding Proteins; D015687:Cell Hypoxia; D002465:Cell Movement; D002478:Cells, Cultured / Q000166:cytology; D003097:Collateral Circulation / Q000502:physiology*; D042783:Endothelial Cells / Q000378:metabolism*; D006614:Hindlimb / Q000098:blood supply*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000502:physiology; D007511:Ischemia / Q000503:physiopathology*; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009389:Neovascularization, Pathologic / Q000503:physiopathology*; D018919:Neovascularization, Physiologic / Q000502:physiology; D051880:Receptors, Notch / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000502:physiology; D020127:Recovery of Function; D012878:Skin Neoplasms / Q000098:blood supply* / Q000139:chemically induced; D014945:Wound Healing / Q000502:physiology; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D042702:Angiopoietin-2; D051792:Basic Helix-Loop-Helix Proteins; D002135:Calcium-Binding Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D051880:Receptors, Notch; D011993:Recombinant Fusion Proteins; D000099162:Endothelial PAS Domain-Containing Protein 1; C519665:DLL4 protein, mouse; C497443:Hif1a protein, mouse