Title | VEGF is essential for hypoxia-inducible factor-mediated neovascularization but dispensable for endothelial sprouting. |
Publication Type | Journal Article |
Year of Publication | 2011 |
Authors | S Oladipupo, S Hu, J Kovalski, J Yao, A Santeford, RE Sohn, R Shohet, K Maslov, LV Wang, and JM Arbeit |
Journal | Proceedings of the National Academy of Sciences of the United States of America |
Volume | 108 |
Issue | 32 |
Start Page | 13264 |
Pagination | 13264 - 13269 |
Date Published | 08/2011 |
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. |
DOI | 10.1073/pnas.1101321108 |
Short Title | Proceedings of the National Academy of Sciences of the United States of America |