Evidence for a monoclonal origin of human atherosclerotic plaques and some implications

Abstract

Comparison of the naturally occurring atherosclerotic plaques of human beings and birds with the reparative response of mammalian aorta to injury led to the consideration of an alternative to the injury repair hypothesis currently in vogue. This was based upon the following considerations: cells of spontaneous lesions differ from cells of normal arterial wall media and also from cells populating a repair site. They differ in size and arrangement of cells, in composition of associated extracellular material. In particular the cells of the plaque are smaller than those of the media and appear to produce abundant collagen and little or no elastin. Intercellular junctions between cells of the plaque are reduced in number or absent. These apparent differences in the cell populations encouraged consideration of the possibility that the focal proliferative lesions of atherosclerosis are either derived from a different group of cells than those populating the media or are an altered cell population, the change being similar to that occurring in benign smooth muscle cell tumors. Benign smooth muscle tumors, uterine leiomyomas, and other preneoplastic lesions appear to originate from a single precursor cell, i.e., are monoclonal in origin. Recent developments in the understanding of somatic cell genetics and the capacity to analyze these in human material made the question concerning the cell composition of plaques susceptible to an answer. Data from 30 plaques from 3 cases and 50 samples of nonplaque intima from 4 cases showed that fibrous caps, even of relatively large plaques, appear to be composed of cells that produce solely or predominately one enzyme type. On the other hand, the arterial media seems regularly to be composed of a mixture of cell types in samples as small as 0.1 cubic mm of tissue. Further experiments provide consistent support of the original data: analysis of 12 more plaques from 4 more cases including one coronary plaque yielded enzyme patterns consistent with a monoclonal character of the plaques against a background of mixtures of the 2 cell types for the intima and inner media. The apparent monoclonal character of the atherosclerotic plaques led to the idea that these proliferative lesions have properties resembling benign neoplasms. One feature of neoplasms expressed by some on culture of their cells in vitro is an apparently infinite capacity to divide. The cells of the atherosclerotic plaques and the cells of the leiomyomas behave in an identical manner under conditions of culture, but both exhibited a finite life span.