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Published August 9, 2011 | Published + Supplemental Material
Journal Article Open

VEGF is essential for hypoxia-inducible factor-mediated neovascularization but dispensable for endothelial sprouting


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:VEGFΔ 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:VEGFΔ 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:VEGFΔ mice. Impaired TetON-HIF-1:VEGFΔ 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.

Additional Information

© 2011 National Academy of Sciences. Edited by Gregg L. Semenza, The Johns Hopkins University School of Medicine, Baltimore, MD, and approved June 24, 2011 (received for review January 26, 2011). Published online before print July 22, 2011. We thank Hans Peter Gerber and Napoleon Ferrara for the gift of the VEGF^(flox/flox) mice, Rick Bruick for the gift of the TRE-HIF-1α^(P402A/P464A/N803A) plasmid for construction of the TRE-HIF-1α^(P402/464A/N803A) transgenic mice, and Adam Glick for the gift of the K5-rtTA transgenic mice. This work was supported by National Institutes of Health Grants R01-CA90722, R01 EB000712, R01 NS46214, R01 EB008085, and U54 CA136398, and the Beatrice Roe Urologic Cancer Fund. Author contributions: S.O., S.H., K.M., L.V.W., and J.M.A. designed research; S.O., S.H., J.K., A.S., and R.E.S. performed research; R.S. and K.M. contributed new reagents/analytic tools; S.O., S.H., J.K., J.Y., L.V.W., and J.M.A. analyzed data; and S.O., S.H., J.Y., L.V.W., and J.M.A. wrote the paper. S.O. and S.H. contributed equally to this work. Conflict of interest statement: L.V.W. has financial interest in Microphotoacoustics, Inc., and Endra, Inc., which, however, did not support this work. Other authors declare no competing financial interest. This Direct Submission article had a prearranged editor. This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1101321108/-/DCSupplemental.

Attached Files

Published - PNAS-2011-Oladipupo-13264-9.pdf

Supplemental Material - pnas.201101321SI.pdf


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