Published Online
on October 25, 2004

A more recent version of this article appeared on November 2, 2004

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Submitted on February 8, 2004
Revised on May 16, 2004
Accepted on July 27, 2004

Hepatocyte Growth Factor Suppresses Vascular Medial Hyperplasia and Matrix Accumulation in Advanced Pulmonary Hypertension of Rats

Masamichi Ono MD, PhD, Yoshiki Sawa MD, PhD^*, Shinya Mizuno PhD, Norihida Fukushima MD, PhD, Hajime Ichikawa MD, Kazuhiko Bessho MD, Toshikazu Nakamura PhD, and Hikaru Matsuda MD, PhD

From the Division of Cardiovascular Surgery, Department of Surgery (M.O., Y.S., N.F., H.I., H.M.), and the Division of Molecular Regenerative Medicine, Department of Regenerative Medicine, Course of Advanced Medicine (S.M., K.B., T.N.), Osaka University Graduate School of Medicine, Osaka, Japan.

^* To whom correspondence should be addressed. E-mail: sawa{at}surg1.med.osaka-u.ac.jp.

Background--Pulmonary hypertension (PH) is a progressive disease characterized by raised pulmonary vascular resistance, thought to be curable only through lung transplantation. Pathophysiologically, proliferation of pulmonary artery smooth muscle cells triggers pulmonary arterial stenosis and/or regurgitation, especially in advanced PH.

Methods and Results--Using a rat model of advanced pulmonary vascular disease produced by injecting monocrotaline, we show that hepatocyte growth factor (HGF) targets pulmonary arterioles and blocks the progression of PH. In these rats, endogenous HGF production was dramatically downregulated during developing experimental PH, but c-Met/HGF receptor was abundant in the medial layers of pulmonary arterioles. HGF gene transfection 2 weeks after the monocrotaline injection resulted in milder medial hyperplasia in lung arterioles and inhibited overgrowth of pulmonary artery smooth muscle cells. Notably, exogenous HGF reduced lung expression levels of endothelin-1 and transforming growth factor-, which are critically involved in PH-linked fibrogenic events. Overall, medial wall thickening of pulmonary arteries was almost completely prevented by HGF, and the total collagen deposition in the lung decreased; both effects contributed to the suppression of pulmonary artery hypertension.

Conclusions--Our results suggest that the loss of endogenous HGF may be a feature of the pathogenesis of PH and that HGF supplementation may minimize pathological lung conditions, even advanced PH.

Key words: gene therapy • pulmonary vasculature • growth factor • remodeling

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