title: VEGF is essential for hypoxia-inducible factor-mediated neovascularization but dispensable for endothelial sprouting.
abstract: Although our understanding of the molecular regulation of adult neovascularization has advanced tremendously, vascular-targeted therapies for tissue ischemia remain suboptimal. The master regulatory transcription factors of the hypoxia-inducible factor (HIF) family are attractive therapeutic targets because they coordinately up-regulate multiple genes controlling neovascularization. Here, we used an inducible model of epithelial HIF-1 activation, the TetON-HIF-1 mouse, to test the requirement for VEGF in HIF-1 mediated neovascularization. TetON-HIF-1, K14-Cre, and VEGF(flox/flox) alleles were combined to create TetON-HIF-1:VEGF(Δ) mice to activate HIF-1 and its target genes in adult basal keratinocytes in the absence of concomitant VEGF. HIF-1 induction failed to produce neovascularization in TetON-HIF-1:VEGF(Δ) mice despite robust up-regulation of multiple proangiogenic HIF targets, including PlGF, adrenomedullin, angiogenin, and PAI-1. In contrast, endothelial sprouting was preserved, enhanced, and more persistent, consistent with marked reduction in Dll4-Notch-1 signaling. Optical-resolution photoacoustic microscopy, which provides noninvasive, label-free, high resolution, and wide-field vascular imaging, revealed the absence of both capillary expansion and arteriovenous remodeling in serially imaged individual TetON-HIF-1:VEGF(Δ) mice. Impaired TetON-HIF-1:VEGF(Δ) neovascularization could be partially rescued by 12-O-tetradecanoylphorbol-13-acetate skin treatment. These data suggest that therapeutic angiogenesis for ischemic cardiovascular disease may require treatment with both HIF-1 and VEGF.
authors.affiliation: Urology Division, Department of Surgery, and Department of Medicine, University of Hawaii 96813, USA.
authors.forename: Sunday
authors.initials: S
authors.lastname: Oladipupo
authors.forename: Song
authors.initials: S
authors.lastname: Hu
authors.forename: Joanna
authors.initials: J
authors.lastname: Kovalski
authors.forename: Junjie
authors.initials: J
authors.lastname: Yao
authors.forename: Andrea
authors.initials: A
authors.lastname: Santeford
authors.forename: Rebecca E
authors.initials: RE
authors.lastname: Sohn
authors.forename: Ralph
authors.initials: R
authors.lastname: Shohet
authors.forename: Konstantin
authors.initials: K
authors.lastname: Maslov
authors.forename: Lihong V
authors.initials: LV
authors.lastname: Wang
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Arbeit
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D017353:Gene Deletion; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D019426:Integrases / Q000378:metabolism; D015603:Keratinocytes / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D055806:Microvessels / Q000187:drug effects / Q000473:pathology; D022423:Myeloid Cells / Q000378:metabolism / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism*; D013752:Tetracycline / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D042461:Vascular Endothelial Growth Factor A; C045073:Cre recombinase; D019426:Integrases; D013752:Tetracycline; D013755:Tetradecanoylphorbol Acetate