Journal Article

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

Kovalski, Joanna, Sohn, Rebecca E, Wang, Lihong V, Santeford, Andrea, Yao, Junjie, Oladipupo, Sunday, Maslov, Konstantin, Shohet, Ralph, Arbeit, Jeffrey M, Hu, Song

2011

Overview

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 VEGFflox/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.

• Publisher: National Academy of Sciences,National Acad Sciences
• Subject: adults / alleles / Angiogenesis / Animals / Biological Sciences / Blood vessels / Cardiovascular disease / Cardiovascular diseases / Cell Proliferation - drug effects / Endothelial cells / Endothelial Cells - drug effects / Endothelial Cells - metabolism / Epithelial Cells - drug effects / Epithelial Cells - metabolism / Epithelial Cells - pathology / epithelium / Gene Deletion / Gene expression / Hypoxia / Hypoxia-Inducible Factor 1, alpha Subunit - metabolism / image analysis / Integrases - metabolism / ischemia / Keratinocytes / Keratinocytes - drug effects / Keratinocytes - metabolism / Mice / microscopy / Microvessels - drug effects / Microvessels - pathology / Myeloid cells / Myeloid Cells - metabolism / Myeloid Cells - pathology / Neovascularization, Pathologic - genetics / Neovascularization, Pathologic - metabolism / Proteins / Renovations / Sprouting / Tetracycline - pharmacology / Tetradecanoylphorbol Acetate - pharmacology / transcription factors / Tumors / Up regulation / Vascular endothelial growth factor / Vascular Endothelial Growth Factor A - metabolism / vascular endothelial growth factors