Potentiated Angiogenic Effect of Scatter Factor/Hepatocyte Growth Factor via Induction of Vascular Endothelial Growth Factor: The Case for Paracrine Amplification of Angiogenesis

Abstract

Background —Scatter factor/hepatocyte growth factor (SF/HGF) is a pleiotropic growth factor that stimulates proliferation and migration of endothelial cells (ECs) via the c- Met receptor, present on ECs as well as other cell types, including smooth muscle cells (SMCs). We studied the effects of recombinant human (rh) SF/HGF in vitro and in vivo in a rabbit model of hindlimb ischemia. We further compared these effects with those of recombinant human vascular endothelial growth factor (rhVEGF 165 ), an EC–specific mitogen. Methods and Results —In vitro, rhSF/HGF and rhVEGF 165 exhibited similar effects on proliferation and migration of ECs. When both cytokines were administered together, the result was an additive effect on EC proliferation and a synergistic effect on EC migration. Application of rhSF/HGF to cultures of human SMCs resulted in the induction of VEGF mRNA and protein. In vivo, administration of rhSF/HGF (500 μg×3) was associated with significant improvements in collateral formation ( P <.001) and regional blood flow ( P <.0005) and with a significant reduction in muscle atrophy ( P <.0001). These effects were significantly more pronounced than those of rhVEGF 165 administered according to the same protocol ( P <.05). Neither remote angiogenesis nor other pathological sequelae were observed with either rhSF/HGF or rhVEGF 165 . Conclusions —The pleiotropic effects of certain growth factors may potentiate angiogenesis via a combination of direct effects on EC proliferation and migration and indirect effects that result in the generation of other potent EC mitogens from non-EC populations. The synergistic effects demonstrated when SF/HGF and VEGF are administered together in vitro may be reproduced in vivo by SF/HGF-induced upregulation of VEGF in vascular SMCs.