Cell population kinetics in atherogenesis. Cell births and losses in intimal cell mass-derived lesions in the abdominal aorta of swine.

Atherosclerotic lesions may arise in a number of different ways. The two most notable, perhaps, are by monocyte infiltration of the intima and by hyperplasia of normally occurring intimal cell masses. This report is limited to the ICM-derived lesion type induced by a hyperlipidemic diet in the abdominal aorta of swine. The HL diet results, by 49 days, in accumulation of lipid in about 50% of the ICM cells and increases in cell division activity, as indicated by tritiated thymidine LI fourfold greater than in ICM of control swine. Cell numbers are not significantly increased over controls at 49 days, but by 90 HL diet days, they have increased to eightfold over control values. Throughout the 90 days, about 95% of the cells in the ICM or ICM-lesions are smooth muscle cells. Monocytes appear to constitute no more than 5% of the cells. Calculated lesion cell deaths are small during the 90 days, and foci of necrosis are rarely found. By scanning electron microscopy, the endothelial cell integrity appears to be maintained even over the ICM-lesions at 90 days. Calculations from tritiated thymidine LI indicate endothelial cell losses equivalent to 50% of the LI, but they are not significantly greater for the HL swine than for controls. We suggest, then, that the lipid in the ICM (or something associated with it) is the most likely candidate for the SMC growth stimulatory agent accounting for the increased tritiated thymidine LI and the great increase in ICM-lesion cell numbers between HL diet days 49 and 90. Platelet- and/or monocyte-derived growth factors may also be involved in some subtle fashion, but this study provides no positive evidence to support this hypothesis. Progression of the ICM-derived lesions to the advanced atheromatous phase by 300 days on HL diet appears to be a much more complex process. By 300 days in the specific experiment cited, approximately 65% of the atherosclerotic lesion volume consisted of lipid-rich calcific necrotic debris; calculated death rates of lesion cells were very high compared to that at 90 days; calculated endothelial cell loss rates were considerably higher than in controls; and, large numbers of monocyte-macrophages were present in many areas generally associated with necrotic foci. These changes in the aggregate suggest a much more complex mode of pathogenesis for progression to advanced stages than for initiation and early development.