15(S)-hydroxyeicosatetraenoic acid-induced angiogenesis requires STAT3-dependent expression of VEGF.
15(S)-Hydroxyeicosatetraenoic acid [15(S)-HETE] activated signal transducer and activator of transcription 3 (STAT3) as measured by its tyrosine phosphorylation, translocation from the cytoplasm to the nucleus, DNA binding, and reporter gene activity in human dermal microvascular endothelial cells (HDMVEC). Inhibition of STAT3 activation via adenovirus-mediated expression of its dominant-negative mutant suppressed 15(S)-HETE-induced HDMVEC migration and tube formation in vitro and aortic ring and Matrigel plug angiogenesis in vivo. 15(S)-HETE induced the expression of vascular endothelial growth factor (VEGF) in a time- and STAT3-dependent manner in HDMVEC. In addition, neutralizing anti-VEGF antibodies blocked 15(S)-HETE-induced HDMVEC migration and tube formation in vitro and aortic ring and Matrigel plug angiogenesis in vivo. Together, these results show for the first time that 15(S)-HETE-induced angiogenesis requires STAT3-dependent expression of VEGF. In view of these findings, it is suggested that eicosanoids, particularly 15(S)-HETE, via its capacity to stimulate angiogenesis, may influence the progression of cancer and vascular disease.
Srivastava
Kalyan
K
Department of Physiology, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA.
Kundumani-Sridharan
Venkatesh
V
Zhang
Baolin
B
Bajpai
Arun K
AK
Rao
Gadiparthi N
GN
D000818:Animals; D001011:Aorta / Q000187:drug effects; D002465:Cell Movement / Q000502:physiology; D003094:Collagen; D004338:Drug Combinations; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000494:pharmacology*; D066298:In Vitro Techniques; D007797:Laminin; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018919:Neovascularization, Physiologic / Q000187:drug effects* / Q000502:physiology; D011509:Proteoglycans; D051381:Rats; D011916:Rats, Inbred F344; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis*
D004338:Drug Combinations; D006893:Hydroxyeicosatetraenoic Acids; D007797:Laminin; D011509:Proteoglycans; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D042461:Vascular Endothelial Growth Factor A; C059485:matrigel; C095134:13-hydroxyeicosatetraenoic acid; D003094:Collagen