{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T14:02:06Z","timestamp":1791036126097,"version":"4.1.0"},"reference-count":58,"publisher":"National Academy of Sciences","issue":"32","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2011,8,9]]},"abstract":"<jats:p>\n                    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\n                    <jats:sup>flox\/flox<\/jats:sup>\n                    alleles were combined to create TetON-HIF-1:VEGF\n                    <jats:sup>\u0394<\/jats:sup>\n                    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\n                    <jats:sup>\u0394<\/jats:sup>\n                    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\n                    <jats:sup>\u0394<\/jats:sup>\n                    mice. Impaired TetON-HIF-1:VEGF\n                    <jats:sup>\u0394<\/jats:sup>\n                    neovascularization could be partially rescued by 12-\n                    <jats:italic>O<\/jats:italic>\n                    -tetradecanoylphorbol-13-acetate skin treatment. These data suggest that therapeutic angiogenesis for ischemic cardiovascular disease may require treatment with both HIF-1 and VEGF.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1101321108","type":"journal-article","created":{"date-parts":[[2011,7,23]],"date-time":"2011-07-23T01:00:09Z","timestamp":1311382809000},"page":"13264-13269","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":154,"title":["VEGF is essential for hypoxia-inducible factor-mediated neovascularization but dispensable for endothelial sprouting"],"prefix":"10.1073","volume":"108","author":[{"given":"Sunday","family":"Oladipupo","sequence":"first","affiliation":[{"name":"Urology Division, Department of Surgery, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Song","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Hawaii, 96813; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joanna","family":"Kovalski","sequence":"additional","affiliation":[{"name":"Urology Division, Department of Surgery, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junjie","family":"Yao","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Hawaii, 96813; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Santeford","sequence":"additional","affiliation":[{"name":"Urology Division, Department of Surgery, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca E.","family":"Sohn","sequence":"additional","affiliation":[{"name":"Urology Division, Department of Surgery, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ralph","family":"Shohet","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering 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