THE MECHANISMS OF HEPATIC SINUSOIDAL ENDOTHELIAL-CELL REGENERATION - A POSSIBLE COMMUNICATION-SYSTEM ASSOCIATED WITH VASCULAR ENDOTHELIAL GROWTH-FACTOR IN LIVER-CELLS

Vascular endothelial growth factor (VEGF) has been shown to induce pro liferation of sinusoidal endothelial cells in primary culture. To eluc idate the mechanisms of sinusoidal endothelial cell regeneration in vi vo, mRNA expression of VEGF and its receptors, flt-1 and KDR/flk-1, we re studied in rat livers. Northern blot analysis revealed that VEGF-mR NA was expressed in hepatocytes immediately after isolation from norma l rats. In contrast, non-parenchymal cells, including sinusoidal endot helial cells, expressed VEGF receptor-mRNA. Vascular endothelial growt h factor-mRNA expression in hepatocytes was decreased during primary c ulture, but increased following a peak of DNA synthesis, induced by ad dition of epidermal growth factor or hepatocyte growth factor to the c ulture medium at 24 h of plating. In a 70% resected rat liver, VEGF-mR NA expression increased with a peak at 72 h after the operation, and m RNA expression of VEGF receptors between 72 and 168 h. In such a liver , mitosis was maximal in hepatocytes at 36 h and in sinusoidal endothe lial cells at 96 h. Also, mRNA expression of both VEGF and its recepto rs was significantly increased in carbon tetrachloride-intoxicated rat liver compared with normal rat liver. Vascular endothelial growth fac tor expression was minimal in Kupffer cells isolated from normal rats, but marked in activated Kupffer cells and hepatic macrophages from th e intoxicated rats. Vascular endothelial growth factor-mRNA expression was also increased in activated stellate cells from these rats and in the cells activated during primary culture compared with quiescent ce lls. We conclude that increased levels of VEGF expression in regenerat ing hepatocytes may contribute to the proliferation of sinusoidal endo thelial cells in partially resected rat liver, probably through VEGF r eceptors up-regulated on the tells. Also, VEGF derived from activated Kupffer cells, hepatic macrophages and stellate cells may be involved in this proliferation in injured rat liver.