Proliferation of endothelial cells in estrogen-stimulated rat liver. A light and electron microscopic cytochemical study.

The mononuclear phagocytes (Kupffer cells) in the normal rat liver can be distinguished from the endothelial cells on the basis of their endogenous peroxidase activity in the endoplasmic reticulum and their exclusive ability to phagocytose large (0.81 mum.) latex particles. Using these cellular markers we have investigated the effects of an estrogen upon the mitotic activity and the ultrastructure of individual types of littoral cells in the rat liver. Adult female rats received a single 10-mg. injection of diethylstilbestrol, and at daily intervals up to 6 days their livers were fixed by perfusion and processed for localization of peroxidase. Mitotic figures were rare in untreated control animals, but dividing littoral cells with both positive and negative peroxidase reaction could be identified. The exclusive localization of injected latex particles in dividing peroxidase-positive cells indicated that peroxidase reaction identified the Kupffer cells not only in the interphase but also during the mitotic division. In estrogen-treated animals there was a sharp rise in the mitotic activity of littoral cells; the activity reached its peak on the 3rd day and returned to normal levels on the 6th day after the initial injection. A breakdown of the dividing cells on the basis of their peroxidase reactivity revealed that nearly the entire population of dividing cells consisted of peroxidase-negative endothelial cells. In addition, numerous hyperactive Kupffer cells containing large phagolysosomes with phagocytosed peripheral blood cells and latex particles were seen. Intermediate cell-types with cytochemical features between Kupffer cells and endothelial cells or between monocytes and Kupffer cells were not encountered. Because of the limited phagocytic capacity of hepatic endothelial cells, our observations would provide morphologic evidence in support of previous physiologic studies, indicating that estrogen treatment has little or no effect upon the particle clearing function of the reticuloendothelial system in rats. The rare but clear demonstration of dividing Kupffer cells in liver sinusoids would indicate that these cells are capable of self-replication in situ. Finally, our observations suggest that estrogens may play an important role in the pathophysiology of endothelial cells.