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


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 G(1)-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.
Abid
Md Ruhul
MR
Department of Medicine, Beth Israel Deaconess Medical Center, RW-663, Boston, MA 02215, USA.
Guo
Shaodong
S
Minami
Takashi
T
Spokes
Katherine C
KC
Ueki
Kohjiro
K
Skurk
Carsten
C
Walsh
Kenneth
K
Aird
William C
WC
D021581:Active Transport, Cell Nucleus / Q000187:drug effects / Q000502:physiology; D000818:Animals; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology; D018797:Cell Cycle Proteins / Q000235:genetics / Q000502:physiology; D002867:Chromones / Q000494:pharmacology; D003331:Coronary Vessels / Q000737:chemistry / Q000166:cytology / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D004730:Endothelium, Vascular / Q000737:chemistry / Q000201:enzymology / Q000378:metabolism / Q000502:physiology*; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D005786:Gene Expression Regulation / Q000502:physiology; D018014:Gene Transfer Techniques; D006801:Humans; D009025:Morpholines / Q000494:pharmacology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt; D011651:Pulmonary Artery / Q000737:chemistry / Q000166:cytology / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000502:physiology; D014471:Umbilical Veins / Q000737:chemistry / Q000166:cytology / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology*
D018797:Cell Cycle Proteins; D002867:Chromones; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004268:DNA-Binding Proteins; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D009025:Morpholines; D009687:Nuclear Proteins; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D042461:Vascular Endothelial Growth Factor A; C085126:FOXO1 protein, human; C499517:FOXO3 protein, human; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C494918:AKT1 protein, human