Sinusoidal Endothelial Cells in Liver Regeneration

Abstract

Vascular endothelial growth factor (VEGF) has been shown to induce proliferation of sinusoidal endothelial cells in primary culture. Northern blot analysis revealed that VEGF mRNA was expressed in hepatocytes immediately after isolation from normal rats. In contrast, nonparenchymal cells, including sinusoidal endothelial cells, expressed mRNAs of VEGF receptors flt-1 and KDR/flk-1, suggesting that a communication system associated with VEGF may contribute to sinusodial endothelial cell regeneration following partial liver resection and liver injury. When rat hepatocytes were cultured on plastic dishes, VEGF mRNA expression diminished following a transient slight increase in its expression. In these cells, the expression increased again following a peak of DNA synthesis when cultured with epidermal growth factor (EGF) or hepatocyte growth factor (HGF). In 70% resected livers, mitosis was maximal at 36h after the operation in hepatocytes and at 96h in sinusoidal endothelial cells. In these livers, VEGF mRNA expression increased in hepatocytes at the G1 phase of the cell cycle and became prominent in the cells which experienced mitosis. Also, mRNA expression of VEGF receptors was up-regulated in the liver following 70% resection. When liver injury was provoked in rats by CC14 administration, mRNA expressions of both VEGF and its receptors were significantly increased in the liver compared with those in normal rat liver. VEGF expression was minimal in Kupffer cells isolated from normal rats, but was marked in activated Kupffer cells and hepatic macrophages from CCl4-intoxicated rats. VEGF mRNA expression was also increased in activated stellate cells from CCl4-intoxicated rats and in stellate cells from normal rats activated by primary culture. Thus, VEGF expressed in regenerating hepatocytes may induce proliferation of sinusoidal endothelial cells in partially resected liver, probably through VEGF receptors up-regulated on the cells. In injured liver, this proliferation may also be produced by VEGF derived from activated Kupffer cells, hepatic macrophages, and stellate cells.