Induction of hypervascularity without leakage or inflammation in transgenic mice overexpressing hypoxia-inducible factor-1α

David A. Elson; Gavin Thurston; L. Eric Huang; David G. Ginzinger; Donald M. McDonald; Randall S. Johnson; Jeffrey M. Arbeit

doi:10.1101/gad.914801

Induction of hypervascularity without leakage or inflammation in transgenic mice overexpressing hypoxia-inducible factor-1α

¹Cancer Genetics Program and ²Genome Analysis Core Facility, UCSF Comprehensive Cancer Center, ³Department of Anatomy and Cardiovascular Research Institute, and ⁴Department of Surgery, University of California, San Francisco, San Francisco, California 94143, USA; ⁵Regeneron Pharmaceuticals, Inc., Tarrytown, New York 10591, USA; ⁶Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-4255, USA; ⁷Biology Department, University of California, San Diego, La Jolla, California 92093-0346, USA

Abstract

Hypoxia-inducible factor-1α (HIF-1α) transactivates genes required for energy metabolism and tissue perfusion and is necessary for embryonic development and tumor explant growth. HIF-1α is overexpressed during carcinogenesis, myocardial infarction, and wound healing; however, the biological consequences of HIF-1α overexpression are unknown. Here, transgenic mice expressing constitutively active HIF-1α in epidermis displayed a 66% increase in dermal capillaries, a 13-fold elevation of total vascular endothelial growth factor (VEGF) expression, and a six- to ninefold induction of each VEGF isoform. Despite marked induction of hypervascularity, HIF-1α did not induce edema, inflammation, or vascular leakage, phenotypes developing in transgenic mice overexpressing VEGF cDNA in skin. Remarkably, blood vessel leakage resistance induced by HIF-1α overexpression was not caused by up-regulation of angiopoietin-1 or angiopoietin-2. Hypervascularity induced by HIF-1α could improve therapy of tissue ischemia.

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↵8 Corresponding author.
E-MAIL jarbeit{at}cc.ucsf.edu; FAX (415) 476-8218.
Article and publication are at http://www.genesdev.org/cgi/doi/10.1101/gad.914801.
- Received May 25, 2001.
- Accepted August 17, 2001.
Cold Spring Harbor Laboratory Press