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(Circulation. 2000;101:2546.)
© 2000 American Heart Association, Inc.

Basic Science Reports

Single Low-Dose Administration of Human Recombinant Hepatocyte Growth Factor Attenuates Intimal Hyperplasia in a Balloon-Injured Rabbit Iliac Artery Model

Satoshi Yasuda, MD; Teruo Noguchi, MD; Masahiro Gohda, MD; Takashi Arai, BS; Nobumasa Tsutsui, BS; Takehisa Matsuda, PhD; Hiroshi Nonogi, MD

From the National Cardiovascular Center, Osaka (S.Y., T.N., M.G., T.M., H.N.), and Tokai Medical Products Inc, Aichi (T.A., N.T.), Japan.

Correspondence to Satoshi Yasuda, MD, Division of Cardiology, Department of Medicine, National Cardiovascular Center, 5-7-1 Fujishiro-dai, Suita, Osaka 565-8565, Japan. E-mail syasuda{at}hsp.ncvc.go.jp

Background—Previous studies have shown that repeated systemic administration of human recombinant hepatocyte growth factor (hrHGF) in mg/kg levels modulates the wound-healing process in various diseases. Recently, HGF has been characterized as one of the most potent endothelial-cell–specific growth factors. We tested our hypothesis that local delivery of hrHGF, even at low µg/kg levels (2 orders of magnitude lower than systemically administered doses), might attenuate neointimal hyperplasia in response to vascular injury via accelerated reendothelialization.

Methods and Results—The iliac artery was denuded in 16 New Zealand White rabbits (3 kg), followed by administration, via a drug delivery catheter, of either hrHGF (10 µg; n=11) or control vehicle (n=5) over 20 minutes. In pilot studies using this device, the drug permeated into the medial tissues, where it persisted for 24 hours. Four weeks after the local delivery of hrHGF, computer-assisted morphometric analysis revealed significant reduction in the intimal area (hrHGF, 0.37±0.21 versus control, 0.68±0.16 mm², mean±SD; P<0.05) but no change in the medial area (hrHGF, 1.03±0.21 versus control, 1.10±0.52 mm²). Scanning electron microscopy revealed extensive endothelialization with regular and confluent endothelial cell layer regeneration in the hrHGF-treated vessels.

Conclusions—Accelerated endothelialization after local delivery of hrHGF, a novel and potent endothelial cell mitogen, effectively attenuates neointimal proliferation even after single low-dose administration. This observation could have potential therapeutic implications in the prevention of restenosis after angioplasty.

Key Words: angioplasty • catheters • endothelium • growth substances • restenosis

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