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on December 1, 2003

Arteriosclerosis, Thrombosis, and Vascular Biology. 2003
Published online before print December 1, 2003, doi: 10.1161/01.ATV.0000110502.10593.06
A more recent version of this article appeared on February 1, 2004
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Right arrow Endothelium/vascular type/nitric oxide

Submitted on September 5, 2003
Accepted on November 19, 2003

Vascular Endothelial Growth Factor Activates PI3K/Akt/Forkhead Signaling in Endothelial Cells

Md. Ruhul Abid ; Shaodong Guo ; Takashi Minami ; Katherine C. Spokes ; Kohjiro Ueki ; Carsten Skurk ; Kenneth Walsh ; and William C. Aird *

From the Department of Medicine, Beth Israel Deaconess Medical Center (M.R.A., S.G., T.M., K.C.S., W.C.A.), and the Joslin Diabetes Center (K.U.), Harvard Medical School, and the Whitaker Cardiovascular Institute (C.S., K.W.), Boston University School of Medicine, Boston, MA.

* To whom correspondence should be addressed. E-mail: waird{at}bidmc.harvard.edu.

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 1 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.




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