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Arterioscler Thromb Vasc Biol. 2008 Nov;28(11):2042-8. doi: 10.1161/ATVBAHA.108.175109. Epub 2008 Sep 11.

Hepatocyte growth factor inhibits VEGF-forkhead-dependent gene expression in endothelial cells.

Author information

1
Department of Medicine, Division Molecular and Vascular Medicine, Center for Vascular Biology Research, Harvard Medical School, Boston, Massachusetts 02215, USA. rabid@bidmc.harvard.edu

Abstract

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.

CONCLUSIONS:

These findings suggest that physiological agonists of PI3K-Akt signaling pathway may modulate VEGF-FKHR/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.

PMID:
18787186
PMCID:
PMC2903228
DOI:
10.1161/ATVBAHA.108.175109
[Indexed for MEDLINE]
Free PMC Article

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