Premium
FIBROBLAST GROWTH FACTOR‐2 IS A DOWNSTREAM MEDIATOR OF PI3K‐AKT SIGNALING IN 14, 15‐EPOXYEICOSATRIENOIC ACID‐INDUCED ANGIOGENESIS
Author(s) -
Rao Gadiparthi N,
Zhang Baolin,
Cao Huiqing
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.5.a1328-c
To determine the efficacy of cytochrome P450 (CYP) 2C9 metabolites of arachidonic acid, namely, 5,6‐, 8,9‐, 11,12‐ and 14,15‐epoxyeicosatrienoic acids (5,6‐EET, 8,9‐EET, 11,12‐EET and 14,15‐EET, respectively), in inducing angiogenesis, we have studied their effects on human dermal microvascular endothelial cell (HDMVEC) tube formation and migration. All four EETs stimulated HDMVEC tube formation and migration in a dose‐dependent manner. Since 14,15‐EET was found to be slightly more efficacious than 5,6‐, 8,9‐ and 11,12‐EETs in stimulating HDMVEC tube formation and migration, we next focused on elucidation of the signaling mechanisms underlying its angiogenic activity. 14,15‐EET stimulated Akt and S6K1 phosphorylation in Src and PI3K‐dependent manner in HDMVEC. Inhibition of Src and PI3K‐Akt‐mTOR signaling by both pharmacological and dominant negative mutant approaches suppressed 14,15‐EET‐induced HDMVEC tube formation and migration in vitro and Matrigel plug angiogenesis in vivo. In addition, 14,15‐EET induced the expression of FGF‐2 in Src and PI3K‐Akt‐dependent and mTOR‐independent manner in HDMVEC. Neutralizing anti‐FGF‐2 antibodies completely suppressed 14,15‐EET‐induced HDMVEC tube formation and migration in vitro and Matrigel plug angiogenesis in vivo. Together, these results show for the first time that Src and PI3K‐Akt signaling via targeting in parallels the FGF‐2 expression and mTOR‐S6K1 activation plays an indispensable role in 14,15‐EET induced angiogenesis.