An essential role for SRC-activated STAT-3 in 14, 15-EET-induced VEGF expression and angiogenesis

Sergey Y. Cheranov, Manjula Karpurapu, Dong Wang, Baolin Zhang, Richard C. Venema, Gadiparthi N. Rao

Research output: Contribution to journalArticle

83 Scopus citations

Abstract

To understand the molecular mechanisms underlying 14,15-epoxyeicosatrienoic acid (14,15-EET)-induced angiogenesis, here we have studied the role of signal transducer and activator of transcription-3 (STAT-3). 14,15-EET stimulated the tyrosine phosphorylation of STAT-3 and its translocation from the cytoplasm to the nucleus in human dermal microvascular endothelial cells (HDMVECs). Adenovirus-mediated delivery of dominant negative STAT-3 substantially inhibited 14,15-EET-induced HDMVEC migration, and tube formation and Matrigel plug angiogenesis. 14,15-EET activated Src, as measured by its tyrosine phosphorylation and blockade of its activation by adenovirus-mediated expression of its dominant negative mutant, significantly attenuated 14,15-EET-induced STAT-3 phosphorylation in HDMVECs and the migration and tube formation of these cells and Matrigel plug angiogenesis. 14,15-EET induced the expression of vascular endothelial cell growth factor (VEGF) in a time- and Src-STAT-3-dependent manner in HDMVECs. Transfac analysis of VEGF promoter revealed the presence of STAT-binding elements and 14,15-EET induced STAT-3 binding to this promoter in vivo, and this interaction was inhibited by suppression of Src-STAT-3 signaling. Neutralizing anti-VEGF antibodies completely blocked 14,15-EET-induced HDMVEC migration and tube formation and Matrigel plug an-giogenesis. These results reveal that Src-dependent STAT-3-mediated VEGF expression is a major mechanism of 14,15-EET-induced angiogenesis.

Original languageEnglish (US)
Pages (from-to)5581-5591
Number of pages11
JournalBlood
Volume111
Issue number12
DOIs
StatePublished - Jun 15 2008

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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    Cheranov, S. Y., Karpurapu, M., Wang, D., Zhang, B., Venema, R. C., & Rao, G. N. (2008). An essential role for SRC-activated STAT-3 in 14, 15-EET-induced VEGF expression and angiogenesis. Blood, 111(12), 5581-5591. https://doi.org/10.1182/blood-2007-11-126680