Hepatocyte growth factor stimulated angiogenesis without inflammation: differential actions between hepatocyte growth factor, vascular endothelial growth factor and basic fibroblast growth factor.

Based on the potent angiogenic effects of hepatocyte growth factor (HGF), therapeutic angiogenesis using human HGF plasmid DNA increased tissue perfusion and reduced symptoms in patients with critical limb ischemia (CLI) in randomized placebo-controlled clinical trials. To explore further the potent angiogenic activity of HGF, the present study compared the effects of HGF, vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) on angiogenesis and vascular inflammation. All of HGF, VEGF and bFGF significantly induced the formation of capillary blood vessel and granulation tissue in the rat paper disc model as an in vivo animal model of angiogenesis. However, although HGF, bFGF and VEGF significantly increased the growth of vascular endothelial cells, bFGF alone, but not HGF or VEGF, significantly increased the growth of vascular smooth muscle cells (VSMCs) in the in vitro proliferation assay. In addition, bFGF, but not HGF or VEGF, significantly activated an essential transcription factor for inflammation, NFκB, and gene expression of its downstream inflammation-related cytokines (IL-8 and MCP-1) in VSMCs, accompanied by an increase in the vascular permeability in the rat paper disc model. Thus, the present results indicated that HGF induced angiogenesis without vascular inflammation, different from bFGF and VEGF. These different properties between HGF, VEGF and bFGF might affect the efficiency of therapeutic angiogenesis.