Alterations in population dynamics of arterial smooth muscle cells during atherogenesis. IV. Evidence for a polyclonal origin of hypercholesterolemic diet induced atherosclerotic lesions in young swine

Abstract

The purpose of this study was to determine whether atherosclerotic lesions developing in young swine fed hypercholesterolemic (HC) diets were monoclonal or polyclonal in origin. The approach involved labeling arterial cells with tritiated thymidine prior to feeding the HC diet. Baseline swine were sacrificed and radioautography studies carried out to determine baseline labeling indices and grain number distributions in media and in intimal cellular masses (cushions). Remaining swine were then fed an HC diet for 30-60 days before sacrificing and making the same type determinations as with the baseline swine on putative active lesions and media. If a lesion arose from a single cell (or multiple unlabeled cells) labeling indices would be expected to be greatly reduced without a change in grain number patterns. This was not observed in any of the 14 putative lesions that were studied. If the lesion arose from divisions by multiple cells including labeled cells one would expect the proportion of cells with a high number of grains to be decreased, those with low numbers to be increased (since with division half the isotope goes to each daughter cell) and this to be reflected in the grain count. This occurred in 9 of the putative lesions, indicating multicellular origin. In 5 there were neither change in grain number distributions nor reduction in labeling indices. Hence, these showed no division activity during the period of study; they were classified as inactive lesions or preexisting cushions and provide no pertinent information for this study. The final conclusion was that all active lesions observed were polyclonal in origin. Further information was obtained by mathematical analysis on number of divisions made by the originally labeled cells; and considerable heterogeneity was observed, with some not dividing at all and others with progeny going through as many as 4 divisions.