Abnormal proliferation of arterial smooth muscle cells characterizes early atherosclerosis in man. Work of the last decade has suggested a role for mitogens of blood cell origin particularly platelet-derived growth factor (PDGF) in initiation of this process. Although release of PDGF probably does occur at sites of intimal denudation, there is increasing evidence that infiltration by mononuclear phagocytes and proliferation of smooth muscle cells begins while the endothelium is still intact. Thus, the initial stimulus for abnormal growth of smooth muscle cells may arise locally within the vascular wall. For example, endothelial cells might release a smooth muscle mitogen in response non-denuding injury or to signals from infiltrating phagocytes (a """"""""paracrine"""""""" model). Under some conditions, smooth muscle cells might produce a stimulus to their own growth (an """"""""autocrine"""""""" model). The recent findings that the c-sis proto-oncogene encodes one chain of PDGF, and that vascular endothelial cells express c-sis lead to the specific hypotheses related to paracrine and autocrine control of vascular wall cell proliferation that we will investigate here. Expression of c-sis in human vascular endothelial and smooth muscle cells can be increased by potentially atherogenic stimuli (e.g., oxidatively modified or unmodified low density lipoprotein, monocyte products such as interleukin 1, or phorbol diesters). Parallel studies will determine whether these conditions injure cells by measurement of indium release and protein synthetic rates. Cells of the human atherosclerotic plaque express c-sis, as determined by in situ hybridization studies of carotid or coronary atheromata, and by analysis of RNA from characterized cultures of cells from these lesions. We have established sources of tissue and culture methods for propagating smooth muscle cells from human atheromata obtained at surgery. The growth-related oncogenes c-myc and/or c-fos can be induced in human vascular endothelial and smooth muscle cells by selective mitogenic or potentially atherogenic stimuli. These studies will help to elucidate the intermediary steps in mitogen action in vascular wall cells.
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