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.
MeSH terms
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Animals
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Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
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Cell Hypoxia / physiology
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Cell Line
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Endothelial Growth Factors / genetics
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Endothelial Growth Factors / metabolism
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Endothelial Growth Factors / pharmacology
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Endothelium, Vascular / cytology
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Endothelium, Vascular / drug effects
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Endothelium, Vascular / metabolism
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Gene Expression Regulation / drug effects
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Humans
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Hypoxia-Inducible Factor 1, alpha Subunit
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Indomethacin / pharmacology
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Ligases / drug effects*
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Ligases / genetics
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Ligases / metabolism
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Lymphokines / drug effects
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Lymphokines / genetics
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Lymphokines / metabolism
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Lymphokines / pharmacology
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Neovascularization, Pathologic / physiopathology
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Neovascularization, Pathologic / prevention & control
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Nitrobenzenes / pharmacology
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Proto-Oncogene Proteins / drug effects
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism
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RNA, Messenger / drug effects
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Receptor Protein-Tyrosine Kinases / drug effects
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Receptor Protein-Tyrosine Kinases / genetics
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Receptor Protein-Tyrosine Kinases / metabolism
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Sulfonamides / pharmacology
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Transcription Factors / drug effects*
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Transcription Factors / genetics
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Transcription Factors / metabolism
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Tumor Suppressor Proteins*
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Ubiquitin / metabolism
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Ubiquitin-Protein Ligases*
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Vascular Endothelial Growth Factor A
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Vascular Endothelial Growth Factor Receptor-1
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Vascular Endothelial Growth Factors
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Von Hippel-Lindau Tumor Suppressor Protein
Substances
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Anti-Inflammatory Agents, Non-Steroidal
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Endothelial Growth Factors
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HIF1A protein, human
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Hypoxia-Inducible Factor 1, alpha Subunit
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Lymphokines
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Nitrobenzenes
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Proto-Oncogene Proteins
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RNA, Messenger
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Sulfonamides
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Transcription Factors
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Tumor Suppressor Proteins
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Ubiquitin
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Vascular Endothelial Growth Factor A
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Vascular Endothelial Growth Factors
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N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide
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Ubiquitin-Protein Ligases
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Von Hippel-Lindau Tumor Suppressor Protein
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Receptor Protein-Tyrosine Kinases
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Vascular Endothelial Growth Factor Receptor-1
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Ligases
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VHL protein, human
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Indomethacin