POTENTIATED ANGIOGENIC EFFECT OF SCATTER FACTOR HEPATOCYTE GROWTH-FACTOR VIA INDUCTION OF VASCULAR ENDOTHELIAL GROWTH-FACTOR - THE CASE FORPARACRINE AMPLIFICATION OF ANGIOGENESIS/

Background-Scatter factor/hepatocyte growth factor (SF/HGF) is a pleio tropic growth factor that stimulates proliferation and migration of en dothelial cells (ECs) via the c-Met receptor, present on ECs as well a s other cell types, including smooth muscle cells (SMCs). We studied t he effects of recombinant human (rh) SF/HGF in vitro and in vivo in a rabbit model of hindlimb ischemia. We further compared these effects w ith those of recombinant human vascular endothelial growth factor (rhV EGF(165)), an EC-specific mitogen. Methods and Results-In vitro, rhSF/ HGF and rhVEGF(165) exhibited similar effects on proliferation and mig ration of ECs. When both cytokines were administered together, the res ult was an additive effect on EC proliferation and a synergistic effec t on EC migration. Application of rhSF/HGF to cultures of human SMCs r esulted in the induction of VEGF mRNA and protein. In vivo, administra tion of rhSF/HGF (500 mu gX3) was associated with significant improvem ents in collateral formation (P<.001) and regional blood now (P<.0005) and with a significant reduction in muscle atrophy (P<.0001). These e ffects were significantly more pronounced than those of rhVEGF(165) ad ministered according to the same protocol (P<.05). Neither remote ango genesis nor other pathological sequelae were observed with either rhSF /HGF or rhVEGF(165). Conclusions-The pleiotropic effects of certain gr owth factors may potentiate angiogenesis via a combination of direct e ffects on EC proliferation and migration and indirect effects that res ult in the generation oi other potent EC mitogens from non-EC populati ons. The synergistic effects demonstrated when SF/HGF and VEGF are adm inistered together in vitro may be reproduced in vivo by SF/HGF-induce d upregulation of VEGF in vascular SMCs.