Journal
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
Volume 28, Issue 11, Pages 2042-U252Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/ATVBAHA.108.175109
Keywords
HGF; VEGF; forkhead; endothelial cells; gene expression
Categories
Funding
- National Institutes of Health [HL077348]
- American Heart Association [0453284N]
- NIBIO
- NEDO
- Ministry of Education, Culture, Sports, Sciences and Technology
- Takeda Science foundation, Japan
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Objective-Recently, we reported that the forkhead transcription factor, FKHR/FOXO1, is required for vascular endothelial growth factor (VEGF)-mediated upregulation of a number of genes in endothelial cells. Here, we tested the hypothesis that hepatocyte growth factor (HGF), a potent activator of PI3K-Akt in endothelial cells, is capable of depleting the nucleus of FKHR/FOXO1 and thus inhibiting VEGF induction of this class of genes. Methods and Results-Incubation of human coronary artery endothelial cells with HGF induced prolonged PI3K/Akt-dependent phosphorylation and nuclear exclusion of FKHR/FOXO1. HGF-mediated inhibition of FKHR/FOXO1 activity resulted in secondary attenuation of VEGF-induced expression of FKHR/FOXO1-dependent genes including vascular cell adhesion molecule-1, manganese superoxide dismutase, endothelial specific molecule-1, CBP/p300 interacting transactivator with ED-rich tail-2, bone morphogenetic protein-2, matrix metalloproteinase (MMP)-10, and MGC5618. At a functional level, preincubation of HGF resulted in inhibition of VEGF-induced vascular cell adhesion molecule (VCAM)-1-mediated monocyte adhesion to endothelial cells. HGF-mediated inhibition of VEGF-inducible VCAM-1 expression and monocyte adhesion was reversed by overexpression of constitutively active phosphorylation-resistant triple mutant (TM)-FKHR. Conclusion-These findings suggest that physiological agonists of PI3K-Akt signaling pathway may modulate VEGFFKHR/FOXO1-dependent gene expression in endothelial cells. The data underscore the importance of the set point of the endothelial cell when considering mechanisms of signal transduction. (Arterioscler Thromb Vasc Biol. 2008; 28: 2042-2048)
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