Vascular endothelial growth factor (VEGF) plays a major role in angiogenesis, which is essential for both healing of injured tissue and proliferation of carcinoma cells. In this study we elucidated the expression and role of VEGF in rat liver regeneration after partial hepatectomy. VEGF expression was mainly detected in periportal hepatocytes and reached a maximal level 48–72 hr after partial hepatectomy by both immunohistochemistry and in situ hybridization. Similarly, immunohistochemistry for Ki-67 showed that the proliferative activity of sinusoidal endothelial cells was highest in the periportal area and reached a maximal level 72 hr after partial hepatectomy. Moreover, neutralization of VEGF significantly inhibited proliferative activity of hepatocytes ( p < 0.0001), as well as sinusoidal endothelial cells ( p < 0.001), at 48 and 96 hr after partial hepatectomy. Conversely, injection of VEGF significantly promoted proliferative activity of hepatocytes ( p < 0.0001) as well as sinusoidal endothelial cells ( p < 0.0005) at 48 hr after partial hepatectomy. These results suggest that VEGF promotes proliferation of hepatocytes through reconstruction of liver sinusoids by proliferation of sinusoidal endothelial cells. Furthermore, these data point to a new therapeutic strategy, the use of VEGF and other hepatocyte growth factors in fulminant or severe acute hepatitis.

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We have established monoclonal antibodies (MAbs) against human vascular endothelial growth factor/vascular permeability factor121 (VEGF/VPF121). Two (MV101 and MV303) of the 28 MAbs neutralized the mitogenic activity of VEGF/VPF121 on human umbilical vein endothelial cells (HUVEC) in a dose-dependent manner. Both of the MAbs reacted to VEGF/VPF121 and also VEGF/VPF165 with somewhat different binding properties in a sandwich-type enzyme-linked immunosorbent assay (ELSIA). The binding of MV101 and MV303 to VEGF/VPF121 was competitive, but MV415, another anti-VEGF/VPF121 MAb without neutralizing activity, did not complete with either of the antibodies. MV101 and MV303 specifically recognized the native form of VEGF/VPF121 and VEGF/VPF165 in Western blotting. They did not react with VEGF/VPF when the antigens were fractionated under reducing conditions. These observations suggested that MV101 and MV303 might recognize the epitopes closely located on the configuration of VEGF/VPF121 molecule and the epitopes recognized by MV101 and MV303 may play an important role in the VEGF/VPF-receptor signal transduction. These MAbs significantly suppressed the growth of a human hepatoma, PLC/PRF/5, in vivo.

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