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Blood, 15 June 2008, Vol. 111, No. 12, pp. 5581-5591.
Prepublished online as a Blood First Edition Paper on April 11, 2008; DOI 10.1182/blood-2007-11-126680.
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Submitted November 30, 2007
Accepted March 12, 2008
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, and Gadiparthi N Rao*
Physiology, UTHSC, Memphis, TN, United States
Pediatrics, Medical College of Georgia, Augusta, GA, United States
* Corresponding author; email: grao{at}physio1.utmem.edu.
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 tanscription-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 (HDMVEC). 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 HDMVEC 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 HDMVEC. 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 angiogenesis. These results reveal that Src-dependent STAT-3-mediated VEGF expression is a major mechanism of 14,15-EET-induced angiogenesis.
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