Atherosclerosis is a fibroproliferative disorder in which the predominant cell type of atherosclerotic lesions, the smooth muscle cell (SMC), undergoes abnormal growth and overproduction of matrix proteins. The regulatory defect responsible for these abnormalities has not been defined. The goal of this project is to compare the regulation of growth and matrix synthesis in normal and atherosclerotic SMC. Known regulators of these parameters will be studied. Particular attention will be given to substances such as glucocorticoids, transforming growth factor-beta and interleukin-l which are known to affect cells from fibroproliferative disorders. The source of normal and atherosclerotic SMC for this study will be the abdominal aorta of the hyperlipidemic pig. To trace the onset of abnormal regulatory patterns, cells isolated from intimal cell masses, the precursors of atherosclerotic lesions, and from more advanced lesions will be compared with normal medial SMC. Since similar regulatory patterns have been observed between cells from fibrotic lesions and their fetal cell counterpart, SMC will also be cultured from fetal or neonatal pig aortas. Fresh tissue specimens will be examined to ascertain whether regulatory patterns observed in culture also occur in vivo. Characterization of differences in regulation of growth and matrix synthesis and of the onset of these changes in an atherosclerotic model that closely resembles this disease in humans should aid in understanding the causes and progression of atherosclerosis in humans.
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