HEPATOCYTE GROWTH-FACTOR IS A NOVEL MEMBER OF THE ENDOTHELIUM-SPECIFIC GROWTH-FACTORS - ADDITIVE STIMULATORY EFFECT OF HEPATOCYTE GROWTH-FACTOR WITH BASIC FIBROBLAST GROWTH-FACTOR BUT NOT WITH VASCULAR ENDOTHELIAL GROWTH-FACTOR

Objective To seek an endothelium-specific growth factor by examining t he mitogenic effects of hepatocyte growth factor (HGF) on endothelial cells and on vascular smooth muscle cells (VSMC). Methods Rat and huma n endothelial cells and VSMC were employed, DNA, RNA and protein synth esis were measured by using [H-3]-thymidine, uridine and leucine. Cocu lture of endothelial cells with VSMC was also performed to study the r ole of endothelial cells. Results Coculture of endothelial cells with VSMC resulted in a significant decrease in DNA synthesis of VSMC. HGF, as well as basic fibroblast growth factor (bFGF), stimulated DNA, RNA and protein synthesis by endothelial cells in a dose-dependent manner , Interestingly, co-incubation of endothelial cells with HGF and bFGF resulted in an additive stimulation of DNA synthesis. Similarly, HGF a nd interleukin-1 alpha and -6 stimulated DNA synthesis by coronary end othelial cells, whereas interleukin-1 beta and transforming growth fac tor-beta (TGF-beta) did not. However, HGF showed markedly different ac tions from bFGF on VSMC growth. bFGF, TGF-beta, interleukin-1 alpha, - 1 beta and -6 stimulated DNA synthesis in VSMC significantly, whereas HGF did not. Finally, we examined the mitogenic effect of HGF on human aortic endothelial cells and VSMC. Incubation with HGF increased DNA synthesis and growth by endothelial cells in a dose-dependent manner, whose degree was significantly greater than those with bFGF, vascular endothelial growth factor (VEGF) and interleukin-6. Addition of HGF an d VEGF showed no additive effect on DNA synthesis in endothelial cells , in contrast to those of bFGF and HGF. On the other hand, bFGF, but n ot HGF and VEGF, stimulated DNA synthesis in VSMC. Conclusion These re sults demonstrate that HGF can exert stimulating effects on endothelia l cell growth, but not on VSMC growth, in an additive manner with bFGF but not with VEGF. These characteristics of HGF as an endothelium-spe cific growth factor may provide the opportunity for a new therapeutic strategy for vascular diseases in which the abnormalities are vasocons triction and pathological growth.