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FASEB J. 2002 Feb;16(2):264-6. Epub 2001 Dec 28.

von Hippel Lindau tumor suppressor and HIF-1alpha: new targets of NSAIDs inhibition of hypoxia-induced angiogenesis.

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  • 1Department of Medicine, Veterans Affairs Medical Center, Long Beach, California 90822, USA.

Abstract

Nonsteroidal anti-inflammatory drugs (NSAIDs) block prostaglandin synthesis and impair healing of gastrointestinal ulcers and growth of colonic tumors, in part, by inhibiting angiogenesis. The mechanisms of this inhibition are incompletely explained. Here we demonstrate that both nonselective (indomethacin) and COX-2-selective (NS-398) NSAIDs inhibit hypoxia-induced in vitro angiogenesis in gastric microvascular endothelial cells via coordinated sequential events: 1) increased expression of the von Hippel-Lindau (VHL) tumor suppressor, which targets proteins for ubiquitination leading to 2) reduced accumulation of hypoxia-inducible factor-1alpha (HIF-1alpha) and, as a result, 3) reduced expression of vascular endothelial growth factor (VEGF) and its specific receptor Flt-1. Because HIF-1alpha is the major trigger for hypoxia-induced activation of the VEGF and Flt-1 genes, this could explain how NSAIDs inhibit hypoxia-induced angiogenesis. Exogenous VEGF and, to a lesser extent, exogenous prostaglandins partly reversed the NSAIDs inhibition of hypoxia-induced angiogenesis. Taken together, these results indicate that NSAIDs inhibit hypoxia-induced angiogenesis in endothelial cells by inhibiting VEGF and Flt-1 expression through increased VHL expression and the resulting ubiquitination and degradation of HIF-1alpha. This action of NSAIDs has both prostaglandin-dependent and prostaglandin-independent components.

PMID:
11772947
DOI:
10.1096/fj.01-0589fje
[PubMed - indexed for MEDLINE]
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