Journal
FREE RADICAL BIOLOGY AND MEDICINE
Volume 39, Issue 10, Pages 1353-1361Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.freeradbiomed.2005.06.015
Keywords
vascular endothelial growth factor; oxidative stress; peroxynitrite; STAT3; HIF-1; vascular endothelial cells; smooth muscle cells; free radicals
Funding
- PHS HHS [R01-NEI-11766, R01-NEI-04618] Funding Source: Medline
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Increased expression of vascular endothelial growth factor (VEGF) has been correlated with increased oxidative stress and formation of peroxynitrite in numerous disease conditions, including diabetic microangiopathy, tumor angiogenesis, and atherosclerosis. In this study we tested the hypothesis that peroxynitrite stimulates VEGF expression. Treatment of rnicrovascular endothelial cells with exogenous peroxynitrite induced a time- and dose-dependent increase in VEGF mRNA, which peaked within I h of treatment at a concentration of 100 mu M. The increase in VEGF mRNA was followed by a significant increase in VEGF protein. To define the molecular mechanisms involved, the effect of peroxynitrite was determined on the activation of two transcription factors known to regulate VEGF expression during hypoxia and tumor angiogenesis-signal transducer and activator of transcription 3 (STAT3) and hypoxia- inducible factor-1 (HIF-1). Peroxynitrite caused activation and nuclear translocation of STAT3, but not HIF-1. Moreover, transduction of endothelial cells with dominant-negative STAT3 abrogated the peroxynitrite-induced increase in VEGF mRNA. The increase in VEGF mRNA was also blocked by inhibitors of transcription and was unaffected by the inhibition of protein synthesis. These results indicate that peroxynitrite causes increased expression of VEGF in vascular endothelial cells by a process that requires the activation of STAT3. (c) 2005 Elsevier Inc. All rights reserved.
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