title: Hypoxia-inducible factor-1 mediates activation of cultured vascular endothelial cells by inducing multiple angiogenic factors.
abstract: Hypoxia-inducible factor-1 (HIF-1) mediates transcriptional activation of vascular endothelial growth factor (VEGF) and other hypoxia-responsive genes. Transgenic expression of a constitutively stable HIF-1alpha mutant increases the number of vascular vessels without vascular leakage, tissue edema, or inflammation. This study aimed to investigate the molecular basis by which HIF-1 mediates the angiogenic response to hypoxia. In primary human endothelial cells, hypoxia, desferrioxamine, or infection with Ad2/HIF-1alpha/VP16, an adenoviral vector encoding a constitutively stable hybrid form of HIF-1alpha, increased the mRNA and protein levels of VEGF, angiopoietin-2 (Ang-2), and angiopoietin-4 (Ang-4). Infection with Ad2/CMVEV (a control vector expressing no transgene) had no effect. Angiopoietin-1 (Ang-1) expression was not detected in human endothelial cells. Ang-4 was also induced by hypoxia or Ad2/HIF-1alpha/VP16 in human cardiac cells, whereas Ang-1 expression remained unchanged. Recombinant Ang-4 protein protected endothelial cells against serum starvation-induced apoptosis and increased cultured endothelial cell migration and tube formation. Ad2/HIF-1alpha/VP16 stimulated endothelial cell proliferation and tube formation. Hypoxia- or Ad2/HIF-1alpha/VP16-induced tube formation was significantly reduced by a Tie-2 inhibitor. These results suggest that HIF-1 mediates the angiogenic response to hypoxia by upregulating the expression of multiple angiogenic factors. Ang-4 can function similarly as Ang-1 and substitute for Ang-1 to participate in hypoxia-induced angiogenesis. Activation of the angiopoietin/Tie-2 system may play a role in the ability of HIF-1 to induce hypervascularity without excessive permeability.
authors.affiliation: Genzyme Corporation, 31 New York Ave, Framingham, Mass 01701-9322, USA.
authors.forename: Midori
authors.initials: M
authors.lastname: Yamakawa
authors.forename: Louis X
authors.initials: LX
authors.lastname: Liu
authors.forename: Taro
authors.initials: T
authors.lastname: Date
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Belanger
authors.forename: Karen A
authors.initials: KA
authors.lastname: Vincent
authors.forename: Geoffrey Y
authors.initials: GY
authors.lastname: Akita
authors.forename: Takayuki
authors.initials: T
authors.lastname: Kuriyama
authors.forename: Seng H
authors.initials: SH
authors.lastname: Cheng
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Gregory
authors.forename: Canwen
authors.initials: C
authors.lastname: Jiang
mesh_terms: D043925:Angiogenesis Inducing Agents / Q000235:genetics* / Q000378:metabolism; D042702:Angiopoietin-2; D042682:Angiopoietins; D017209:Apoptosis / Q000187:drug effects; D001808:Blood Vessels / Q000187:drug effects / Q000254:growth & development; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D015687:Cell Hypoxia; D002463:Cell Membrane Permeability / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D003676:Deferoxamine / Q000494:pharmacology; D016228:Endothelial Growth Factors / Q000235:genetics / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation / Q000187:drug effects; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D006801:Humans; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D008222:Lymphokines / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology*; D000072483:Placenta Growth Factor; D010982:Platelet-Derived Growth Factor / Q000235:genetics / Q000378:metabolism; D011257:Pregnancy Proteins / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D042787:Receptor, TIE-2; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics / Q000378:metabolism; D042442:Vascular Endothelial Growth Factors
chemical_list: D043925:Angiogenesis Inducing Agents; D042702:Angiopoietin-2; D042682:Angiopoietins; D004268:DNA-Binding Proteins; D016228:Endothelial Growth Factors; C497442:HIF1A protein, human; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D009687:Nuclear Proteins; C000608036:PGF protein, human; D010982:Platelet-Derived Growth Factor; D011257:Pregnancy Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; C118117:angiopoietin 4; D000072483:Placenta Growth Factor; D020794:Receptor Protein-Tyrosine Kinases; D042787:Receptor, TIE-2; D040281:Vascular Endothelial Growth Factor Receptor-1; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D003676:Deferoxamine