The intima: development and monoclonal responses to injury

Most current concepts of the biology of atherosclerosis and restenosis are highly hypothetical, based on studies of the growth properties of medial smooth muscle cells. These cells are clearly different in many ways from intimal smooth muscle cells. Indeed, in a recent compilation of the literature, we found approximately 80 genes that show constitutive differences in expression levels between intimal versus medial smooth muscle cells [122]. An important example of the possible importance of the intimal cell may be the still poorly-understood mechanism in restenosis. If this process is not due to simple neointimal formation, it may well be the result of the remodeling properties of pre-existing intimal cells. Perhaps, like fibroblasts in skin, intimal cells respond to injury by forming and then contracting a scar. Unfortunately, the literature contains little evidence on the properties of intimal or plaque smooth muscle in any species except the rat. In part, this lack of cell culture data on human plaque smooth muscle cells reflects the short replicative life span of these cells. This phenomenon may reflect the high apoptotic rate of these cells; indeed, recent in vivo studies show extensive apoptosis in the plaque smooth muscle cells in tissue sections as well [123-125]. Finally, while the observation of monoclonality has been neglected in recent reviews, those data have been reproduced several times, including recently in this laboratory (Murry et al., unpublished data). Any competent hypothesis of atherosclerosis must account for monoclonality. As noted above, it is possible that monoclonality of the intima is a normal part of development of the intima. This is a critical hypothesis, since the alternatives, i.e., existence of a proliferative subset or benign transformation of plaque smooth muscle cells both imply unique properties of the plaque smooth muscle cell that would become prime targets in understanding the ontogeny of this most important vascular disease.