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

Publication ,  Journal Article
Oladipupo, S; Hu, S; Kovalski, J; Yao, J; Santeford, A; Sohn, RE; Shohet, R; Maslov, K; Wang, LV; Arbeit, JM
Published in: Proceedings of the National Academy of Sciences of the United States of America
August 2011

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.

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Published In

Proceedings of the National Academy of Sciences of the United States of America

DOI

EISSN

1091-6490

ISSN

0027-8424

Publication Date

August 2011

Volume

108

Issue

32

Start / End Page

13264 / 13269

Related Subject Headings

  • Vascular Endothelial Growth Factor A
  • Tetradecanoylphorbol Acetate
  • Tetracycline
  • Neovascularization, Pathologic
  • Myeloid Cells
  • Microvessels
  • Mice
  • Keratinocytes
  • Integrases
  • Hypoxia-Inducible Factor 1, alpha Subunit
 

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Oladipupo, S., Hu, S., Kovalski, J., Yao, J., Santeford, A., Sohn, R. E., … Arbeit, J. M. (2011). VEGF is essential for hypoxia-inducible factor-mediated neovascularization but dispensable for endothelial sprouting. Proceedings of the National Academy of Sciences of the United States of America, 108(32), 13264–13269. https://doi.org/10.1073/pnas.1101321108
Oladipupo, Sunday, Song Hu, Joanna Kovalski, Junjie Yao, Andrea Santeford, Rebecca E. Sohn, Ralph Shohet, Konstantin Maslov, Lihong V. Wang, and Jeffrey M. Arbeit. “VEGF is essential for hypoxia-inducible factor-mediated neovascularization but dispensable for endothelial sprouting.Proceedings of the National Academy of Sciences of the United States of America 108, no. 32 (August 2011): 13264–69. https://doi.org/10.1073/pnas.1101321108.
Oladipupo S, Hu S, Kovalski J, Yao J, Santeford A, Sohn RE, et al. VEGF is essential for hypoxia-inducible factor-mediated neovascularization but dispensable for endothelial sprouting. Proceedings of the National Academy of Sciences of the United States of America. 2011 Aug;108(32):13264–9.
Oladipupo, Sunday, et al. “VEGF is essential for hypoxia-inducible factor-mediated neovascularization but dispensable for endothelial sprouting.Proceedings of the National Academy of Sciences of the United States of America, vol. 108, no. 32, Aug. 2011, pp. 13264–69. Epmc, doi:10.1073/pnas.1101321108.
Oladipupo S, Hu S, Kovalski J, Yao J, Santeford A, Sohn RE, Shohet R, Maslov K, Wang LV, Arbeit JM. VEGF is essential for hypoxia-inducible factor-mediated neovascularization but dispensable for endothelial sprouting. Proceedings of the National Academy of Sciences of the United States of America. 2011 Aug;108(32):13264–13269.
Journal cover image

Published In

Proceedings of the National Academy of Sciences of the United States of America

DOI

EISSN

1091-6490

ISSN

0027-8424

Publication Date

August 2011

Volume

108

Issue

32

Start / End Page

13264 / 13269

Related Subject Headings

  • Vascular Endothelial Growth Factor A
  • Tetradecanoylphorbol Acetate
  • Tetracycline
  • Neovascularization, Pathologic
  • Myeloid Cells
  • Microvessels
  • Mice
  • Keratinocytes
  • Integrases
  • Hypoxia-Inducible Factor 1, alpha Subunit