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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:2042.)
© 2008 American Heart Association, Inc.

Cell Biology/Signaling

Hepatocyte Growth Factor Inhibits VEGF-Forkhead–Dependent Gene Expression in Endothelial Cells

Md. Ruhul Abid; Robert J. Nadeau; Katherine C. Spokes; Takashi Minami; Dan Li; Shou-Ching Shih; William C. Aird

From the Center for Vascular Biology Research (M.R.A., R.J.N., K.C.S., W.C.A.), Department of Medicine and Division of Molecular and Vascular Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Mass; the Research Center for Advanced Science and Technology (T.M.), University of Tokyo, Japan; the Department of Pathology (D.L., S.-C.S.), Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Mass.

Correspondence to Ruhul Abid, MD, PhD, Molecular and Vascular Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, E/RW-663, 330 Brookline Avenue, Boston, MA 02215. E-mail rabid{at}bidmc.harvard.edu

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 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.

Key Words: HGF • VEGF • forkhead • endothelial cells • gene expression

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