Peroxynitrite increases VEGF expression in vascular endothelial cells via STAT3

Daniel H. Platt, Manuela Bartoli, Azza B. El-Remessy, Mohamed Al-Shabrawey, Tahira Lemtalsi, David J Fulton, Ruth B Caldwell

Research output: Contribution to journalArticle

51 Citations (Scopus)

Abstract

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 microvascular endothelial cells with exogenous peroxynitrite induced a time- and dose-dependent increase in VEGF mRNA, which peaked within 1 h of treatment at a concentration of 100 μM. 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.

Original languageEnglish (US)
Pages (from-to)1353-1361
Number of pages9
JournalFree Radical Biology and Medicine
Volume39
Issue number10
DOIs
StatePublished - Nov 15 2005

Fingerprint

STAT3 Transcription Factor
Peroxynitrous Acid
Endothelial cells
Vascular Endothelial Growth Factor A
Endothelial Cells
Hypoxia-Inducible Factor 1
Messenger RNA
Chemical activation
Tumors
Diabetic Angiopathies
Oxidative stress
Transcription
Atherosclerosis
Proteins
Oxidative Stress
Transcription Factors

Keywords

  • Free radicals
  • HIF-1
  • Oxidative stress
  • Peroxynitrite
  • STAT3
  • Smooth muscle cells
  • Vascular endothelial cells
  • Vascular endothelial growth factor

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

Cite this

Peroxynitrite increases VEGF expression in vascular endothelial cells via STAT3. / Platt, Daniel H.; Bartoli, Manuela; El-Remessy, Azza B.; Al-Shabrawey, Mohamed; Lemtalsi, Tahira; Fulton, David J; Caldwell, Ruth B.

In: Free Radical Biology and Medicine, Vol. 39, No. 10, 15.11.2005, p. 1353-1361.

Research output: Contribution to journalArticle

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