Roles of endothelin-1 in normal and fibrotic rat livers

Immunocytochemical localization of big endothelin-1(big ET-1)，ET-1 and ET receptor A and B(ET D 2 A D 2 And ET D 2 B I D 2)，and gene expression of preproET-1 mRNA were examined on the rat liver vasculature.Immunoreactivities for big ET-1and for ET-1were preferentially seen along the endothelium of inter16bular veins(IV)。Expression of preproET-1 mRNA was detected in the endothelium.Immunoelectron microscopy showed that rough endoplasmic cisterns were immunoreactive for big ET-1，while Weibel-Palade bodies，a storage site for ET-1，were immunoreactive for ET-1in endothelial cells of IV.The plasma membrane of hepatic stellate cells(HSCs)was immunoreactive for both ET-D2A，D2and ET Immunoelectron microscopy showed that rough endoplasmic cells。These findings suggest that endothelial cells of IV are the major site of synthesis of ET-1，and that ET-1 receptor-mediated HSC contraction is involved in the regulation of hepatic sinusoidal blood flow as previously cited in mammalian liver cirrhosis.We also examined immunocytochemical localizations of big ET-1and ET-1on fibrotic livers of the thioacetamide-treated rats.Immunoreactivities for big ET-1and for ET-1were preferentially seen in HSCs which exhibit characteristics of myofibroblasts。Immunoelectron microscopy showed that rough endoplasmic cisterns of the HSCs Were immunoreactive for big ET-1。Since it was already reported by several biochemists that ET-1accelerates the synthetic ability of collagen fibers in HSCs，these results indicate that ET-1，synthesized in HSCs，is involved in the progress of liver fibrosis in an autocrine fashon。

Immunocytochemical localization of big endothelin-1 (big ET-1), ET-1 and ET receptor A and B (ETィイD2AィエD2 and ETィイD2BィエD2), and gene expression of preproET-1 mRNA were examined on the rat liver vasculature. Immunoreactivities for big ET-1 and for ET-1 were preferentially seen along the endothelium of inter16bular veins (IV). Expression of preproET-1 mRNA was detected in the endothelium. Immunoelectron microscopy showed that rough endoplasmic cisterns were immunoreactive for big ET-1, while Weibel-Palade bodies, a storage site for ET-1, were immunoreactive for ET-1 in endothelial cells of IV. The plasma membrane of hepatic stellate cells (HSCs) was immunoreactive for both ETィイD2AィエD2 and ETィイD2BィエD2 receptor antibodies. These findings suggest that endothelial cells of IV are the major site of synthesis of ET-1, and that ET-1 receptor-mediated HSC contraction is involved in the regulation of hepatic sinusoidal blood flow as previously cited in mammalian liver cirrhosis. We also examined immunocytochemical localizations of big ET-1 and ET-1 on fibrotic livers of the thioacetamide-treated rats. Immunoreactivities for big ET-1 and for ET-1 were preferentially seen in HSCs which exhibit characteristics of myofibroblasts. Immunoelectron microscopy showed that rough endoplasmic cisterns of the HSCs Were immunoreactive for big ET-1. Since it was already reported by several biochemists that ET-1 accelerates the synthetic ability of collagen fibers in HSCs, these results indicate that ET-1, synthesized in HSCs, is involved in the progress of liver fibrosis in an autocrine fashon.