This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 24/2/294    most recent 01.ATV.0000110502.10593.06v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Abid, Md. R. Articles by Aird, W. C. Search for Related Content PubMed PubMed Citation Articles by Abid, Md. R. Articles by Aird, W. C. Pubmed/NCBI databases Gene GEO Profiles HomoloGene UniGene Compound via MeSH Substance via MeSH Related Collections Endothelium/vascular type/nitric oxide

(Arteriosclerosis, Thrombosis, and Vascular Biology. 2004;24:294.)
© 2004 American Heart Association, Inc.

Vascular Biology

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; 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.), 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.

Correspondence to William C. Aird, Beth Israel Deaconess Medical Center, RW-663, Boston, MA 02215. 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 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 p27^kip1. 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.

Key Words: vascular endothelial growth factor • forkhead • endothelial cells • PI3K

This article has been cited by other articles:

				J. A. Garcia and D. Danielpour Mammalian target of rapamycin inhibition as a therapeutic strategy in the management of urologic malignancies Mol. Cancer Ther., June 1, 2008; 7(6): 1347 - 1354. [Abstract] [Full Text] [PDF]

				C. Rask-Madsen and G. L. King Differential Regulation of VEGF Signaling by PKC-{alpha} and PKC-{epsilon} in Endothelial Cells Arterioscler. Thromb. Vasc. Biol., May 1, 2008; 28(5): 919 - 924. [Abstract] [Full Text] [PDF]

				K. N. Papanicolaou, Y. Izumiya, and K. Walsh Forkhead Transcription Factors and Cardiovascular Biology Circ. Res., January 4, 2008; 102(1): 16 - 31. [Abstract] [Full Text] [PDF]

				J. Lu, W. Jiang, J.-H. Yang, P.-Y. Chang, J. P. Walterscheid, H.-H. Chen, M. Marcelli, D. Tang, Y.-T. Lee, W. S.L. Liao, et al. Electronegative LDL Impairs Vascular Endothelial Cell Integrity in Diabetes by Disrupting Fibroblast Growth Factor 2 (FGF2) Autoregulation Diabetes, January 1, 2008; 57(1): 158 - 166. [Abstract] [Full Text] [PDF]

				Md. R. Abid, K. C. Spokes, S.-C. Shih, and W. C. Aird NADPH Oxidase Activity Selectively Modulates Vascular Endothelial Growth Factor Signaling Pathways J. Biol. Chem., November 30, 2007; 282(48): 35373 - 35385. [Abstract] [Full Text] [PDF]

				O. Dormond, J. C. Madsen, and D. M. Briscoe The Effects of mTOR-Akt Interactions on Anti-apoptotic Signaling in Vascular Endothelial Cells J. Biol. Chem., August 10, 2007; 282(32): 23679 - 23686. [Abstract] [Full Text] [PDF]

				Md. R. Abid, S.-C. Shih, H. H. Otu, K. C. Spokes, Y. Okada, D. T. Curiel, T. Minami, and W. C. Aird A Novel Class of Vascular Endothelial Growth Factor-responsive Genes That Require Forkhead Activity for Expression J. Biol. Chem., November 17, 2006; 281(46): 35544 - 35553. [Abstract] [Full Text] [PDF]

				C. Daly, E. Pasnikowski, E. Burova, V. Wong, T. H. Aldrich, J. Griffiths, E. Ioffe, T. J. Daly, J. P. Fandl, N. Papadopoulos, et al. Angiopoietin-2 functions as an autocrine protective factor in stressed endothelial cells PNAS, October 17, 2006; 103(42): 15491 - 15496. [Abstract] [Full Text] [PDF]

				M. Dance, A. Montagner, A. Yart, B. Masri, Y. Audigier, B. Perret, J.-P. Salles, and P. Raynal The Adaptor Protein Gab1 Couples the Stimulation of Vascular Endothelial Growth Factor Receptor-2 to the Activation of Phosphoinositide 3-Kinase J. Biol. Chem., August 11, 2006; 281(32): 23285 - 23295. [Abstract] [Full Text] [PDF]

				M. Fosbrink, F. Niculescu, V. Rus, M. L. Shin, and H. Rus C5b-9-induced Endothelial Cell Proliferation and Migration Are Dependent on Akt Inactivation of Forkhead Transcription Factor FOXO1 J. Biol. Chem., July 14, 2006; 281(28): 19009 - 19018. [Abstract] [Full Text] [PDF]

				C. Huang, J. Li, L. Song, D. Zhang, Q. Tong, M. Ding, L. Bowman, R. Aziz, and G. D. Stoner Black Raspberry Extracts Inhibit Benzo(a)Pyrene Diol-Epoxide-Induced Activator Protein 1 Activation and VEGF Transcription by Targeting the Phosphotidylinositol 3-Kinase/Akt Pathway Cancer Res., January 1, 2006; 66(1): 581 - 587. [Abstract] [Full Text] [PDF]

				Md. R. Abid, K. Yano, S. Guo, V. I. Patel, G. Shrikhande, K. C. Spokes, C. Ferran, and W. C. Aird Forkhead Transcription Factors Inhibit Vascular Smooth Muscle Cell Proliferation and Neointimal Hyperplasia J. Biol. Chem., August 19, 2005; 280(33): 29864 - 29873. [Abstract] [Full Text] [PDF]

				Md. R. Abid, I. G. Schoots, K. C. Spokes, S.-Q. Wu, C. Mawhinney, and W. C. Aird Vascular Endothelial Growth Factor-mediated Induction of Manganese Superoxide Dismutase Occurs through Redox-dependent Regulation of Forkhead and I{kappa}B/NF-{kappa}B J. Biol. Chem., October 15, 2004; 279(42): 44030 - 44038. [Abstract] [Full Text] [PDF]

				S. C. Fagan, D. C. Hess, E. J. Hohnadel, D. M. Pollock, and A. Ergul Targets for Vascular Protection After Acute Ischemic Stroke Stroke, September 1, 2004; 35(9): 2220 - 2225. [Abstract] [Full Text] [PDF]

				T. Furuyama, K. Kitayama, Y. Shimoda, M. Ogawa, K. Sone, K. Yoshida-Araki, H. Hisatsune, S.-i. Nishikawa, K. Nakayama, K. Nakayama, et al. Abnormal Angiogenesis in Foxo1 (Fkhr)-deficient Mice J. Biol. Chem., August 13, 2004; 279(33): 34741 - 34749. [Abstract] [Full Text] [PDF]

				C. Daly, V. Wong, E. Burova, Y. Wei, S. Zabski, J. Griffiths, K.-M. Lai, H. C. Lin, E. Ioffe, G. D. Yancopoulos, et al. Angiopoietin-1 modulates endothelial cell function and gene expression via the transcription factor FKHR (FOXO1) Genes & Dev., May 1, 2004; 18(9): 1060 - 1071. [Abstract] [Full Text] [PDF]