Single low-dose administration of human recombinant hepatocyte growth factor attenuates intimal hyperplasia in a balloon-injured rabbit iliac artery model

Abstract

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.