Vascular endothelial growth factor activates PI3K/Akt/forkhead signaling in endothelial cells

MR Abid, S Guo, T Minami, KC Spokes… - … , and vascular biology, 2004 - Am Heart Assoc
MR Abid, S Guo, T Minami, KC Spokes, K Ueki, C Skurk, K Walsh, WC Aird
Arteriosclerosis, thrombosis, and vascular biology, 2004Am Heart Assoc
Objective—Vascular endothelial growth factor (VEGF) is a potent angiogenic growth factor
that promotes endothelial cell (EC) survival, migration, and permeability. The forkhead
transcription factors FKHR, FKHRL1, and AFX are mammalian orthologues of DAF-16, a
forkhead protein that controls longevity in Caenorhabditis elegans. In this study, we
examined whether VEGF is coupled to phosphatidyl inositol 3-kinase (PI3K)/Akt/forkhead in
ECs. Methods and Results—We demonstrate that human ECs express members of the …
Objective— Vascular endothelial growth factor (VEGF) is a potent angiogenic growth factor that promotes endothelial cell (EC) survival, migration, and permeability. The forkhead transcription factors FKHR, FKHRL1, and AFX are mammalian orthologues of DAF-16, a forkhead protein that controls longevity in Caenorhabditis elegans. In this study, we examined whether VEGF is coupled to phosphatidyl inositol 3-kinase (PI3K)/Akt/forkhead in ECs.
Methods and Results— We demonstrate that human ECs express members of the forkhead family (FKHR, FKHRL1, and AFX) and that VEGF modulates the phosphorylation, subcellular localization, and transcriptional activity of one or more of these isoforms by a PI3K/Akt signaling pathway. VEGF inhibited EC apoptosis, promoted DNA synthesis and the G1-to-S transition, and reduced expression of the cyclin-dependent kinase inhibitor p27kip1. Each of these effects was blocked by the PI3K inhibitor LY294002 or by a phosphorylation-resistant mutant of FKHRL1, but not by wild-type FKHRL1.
Conclusions— These results suggest that VEGF signaling in ECs is coupled to forkhead transcription factors through a PI3K/Akt-dependent pathway.
Am Heart Assoc