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

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...

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Bibliographic Details
Published in:Blood 2008-06, Vol.111 (12), p.5581-5591
Main Authors: Cheranov, Sergey Y., Karpurapu, Manjula, Wang, Dong, Zhang, Baolin, Venema, Richard C., Rao, Gadiparthi N.
Format: Article
Language:English
Subjects:
8,11,14-Eicosatrienoic Acid - analogs & derivatives
8,11,14-Eicosatrienoic Acid - pharmacology
Aorta - cytology
Biological and medical sciences
Cell Movement - drug effects
Cell Movement - physiology
Cell physiology
Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes
Cells, Cultured
Collagen
Drug Combinations
Endothelial Cells - cytology
Endothelial Cells - physiology
Fundamental and applied biological sciences. Psychology
Gene Expression - drug effects
Gene Expression - physiology
Hemostasis, Thrombosis, and Vascular Biology
Humans
Laminin
Molecular and cellular biology
Myocytes, Smooth Muscle - cytology
Myocytes, Smooth Muscle - physiology
Neovascularization, Physiologic - drug effects
Neovascularization, Physiologic - physiology
Phosphorylation - drug effects
Proteoglycans
Signal Transduction - drug effects
Signal Transduction - physiology
src-Family Kinases - metabolism
STAT3 Transcription Factor - metabolism
Vascular Endothelial Growth Factor A - genetics
Vascular Endothelial Growth Factor A - metabolism
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Summary: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 angiogenesis. These results reveal that Src-dependent STAT-3–mediated VEGF expression is a major mechanism of 14,15-EET–induced angiogenesis.
ISSN:0006-4971
1528-0020
DOI:10.1182/blood-2007-11-126680