Atherogenesis during low level hypercholesterolemia in the nonhuman primate. I. Fatty streak formation.

Abstract

Although a large body of data is available concerning atherogenesis in animals maintained at high levels of hypercholesterolemia, little data are available for animals maintained at lower levels of hypercholesterolemia for longer periods of time, closer to those observed in humans. The chronologic sequence of cellular events and interactions that occur during the formation of the lesions of atherosclerosis was investigated during relatively low level hypercholesterolemia (200 to 400 mg/dl) in a series of nonhuman primates (Macaca nemestrina). The arterial tree of each animal was examined by light microscopy and scanning and transmission electron microscopy. Immunohistochemical staining with monoclonal antibodies specific for smooth muscle cells, monocyte-macrophages, and T-lymphocytes was performed to analyze the cellular composition of the lesions. After 6 months of low level hypercholesterolemia, the surface of the aorta contained large numbers of adherent leukocytes, many of which were in the process of entering the artery. This resulted in irregularly shaped nodular elevations, or fatty streaks, preferentially located at branch sites and bifurcations. The fatty streaks consisted of intimal accumulations of numerous lipid-laden macrophages together with relatively small numbers of T-lymphocytes. With lesion progression, the thickness of the fatty streaks increased, and their surfaces became irregular and frequently showed disruptions of covering endothelial cells resulting in exposure of subendothelial macrophages. Platelet microthrombi were observed over some of the exposed macrophages at some branches or bifurcations in every animal studied. These observations made during the early phases of atherosclerosis lesion formation are virtually identical to those described in our previous reports in high level hypercholesterolemic nonhuman primates (600 to 1000 mg/dl) with the exception that the changes occurred more slowly in the lower levels of hypercholesterolemia.