Published Online
on December 1, 2008

A more recent version of this article appeared on January 1, 2009

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Submitted on July 30, 2008
Revised on August 24, 2008

Hepatocyte Growth Factor, but not Vascular Endothelial Growth Factor, Attenuates Angiotensin II–Induced Endothelial Progenitor Cell Senescence

Fumihiro Sanada; Yoshiaki Taniyama; Junya Azuma; Kazuma Iekushi; Norio Dosaka; Toyohiko Yokoi; Nobutaka Koibuchi; Hiroshi Kusunoki; Yoshifusa Aizawa; and Ryuichi Morishita^*

From the Departments of Clinical Gene Therapy (F.S., Y.T., J.A., K.I., N.D., H.K., R.M.), and Geriatric Medicine and Nephrology (Y.T., J.A., K.I., N.D., T.Y., H.K.), Osaka University Graduate School of Medicine, Osaka; Department of Cardiology (F.S., Y.A.), Niigata University Graduate School of Medicine, Niigata; and the Department of Advanced Clinical Science and Therapeutics (N.K.), Graduate School of Medicine, University of Tokyo, Tokyo, Japan.

^* To whom correspondence should be addressed. E-mail: morishit{at}cgt.med.osaka-u.ac.jp.

Abstract—Although both hepatocyte growth factor (HGF) and vascular endothelial growth factor (VEGF) are potent angiogenic growth factors in animal models of ischemia, their characteristics are not the same in animal experiments and clinical trials. To elucidate the discrepancy between HGF and VEGF, we compared the effects of HGF and VEGF on endothelial progenitor cells under angiotensin II stimulation, which is a well-known risk factor for atherosclerosis. Here, we demonstrated that HGF, but not VEGF, attenuated angiotensin II–induced senescence of endothelial progenitor cells through a reduction of oxidative stress by inhibition of the phosphatidylinositol-3,4,5-triphosphate/rac1 pathway. Potent induction of neovascularization of endothelial progenitor cells by HGF, but not VEGF, under angiotensin II was also confirmed by in vivo experiments using several models, including HGF transgenic mice.

Key words: HGF • VEGF • angiotensin II • EPC • senescence • oxidative stress

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