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, Rao Gadiparthi

Research output: Contribution to journalArticle

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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

Fingerprint

STAT3 Transcription Factor
Endothelial cells
Cell growth
Vascular Endothelial Growth Factor A
Intercellular Signaling Peptides and Proteins
Endothelial Cells
Phosphorylation
Skin
Cell Movement
Adenoviridae
Tyrosine
14,15-epoxy-5,8,11-eicosatrienoic acid
Cytoplasm
Chemical activation
Cells
Antibodies

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

An essential role for SRC-activated STAT-3 in 14, 15-EET-induced VEGF expression and angiogenesis. / Cheranov, Sergey Y.; Karpurapu, Manjula; Wang, Dong; Zhang, Baolin; Venema, Richard C.; Gadiparthi, Rao.

In: Blood, Vol. 111, No. 12, 15.06.2008, p. 5581-5591.

Research output: Contribution to journalArticle

Cheranov, Sergey Y. ; Karpurapu, Manjula ; Wang, Dong ; Zhang, Baolin ; Venema, Richard C. ; Gadiparthi, Rao. / An essential role for SRC-activated STAT-3 in 14, 15-EET-induced VEGF expression and angiogenesis. In: Blood. 2008 ; Vol. 111, No. 12. pp. 5581-5591.
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