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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Kovalski, Joanna Arbeit, Jeffrey M. Santeford, Andrea Sohn, Rebecca E. Yao, Junjie Oladipupo, Sunday Maslov, Konstantin Shohet, Ralph Hu, Song Wang, Lihong V. |
| Description | Author Affiliation: Oladipupo S ( Urology Division, Department of Surgery, and Department of Medicine, University of Hawaii 96813, USA.); |
| 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. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 32 |
| Volume Number | 108 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 2011-08-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Endothelial Cells Metabolism Hypoxia-Inducible Factor 1, Alpha Subunit Neovascularization, Pathologic Vascular Endothelial Growth Factor A Animals Cell Proliferation Drug Effects Epithelial Cells Pathology Gene Deletion Integrases Keratinocytes Mice Microvessels Myeloid Cells Genetics Tetracycline Pharmacology Tetradecanoylphorbol Acetate Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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