The fundamental purpose of these studies is to identify the growth factors that stimulate proliferation in blood vessel wall cell types and to determine the mechanisms by which they exert their effects. Cultured porcine aortic smooth muscle and endothelial cells will be used to determine the target cell actions of several mitogens. Smooth muscle cells appear to autoregulate their rates or replication in culture and this autoregulation is partially controlled by the cellular secretion of a somatomedin (Sm) like peptide. Studies will be initiated to determine if blocking the secretion of the Sm-like peptide with a specific monoclonal anti-Sm-C antibody alters the smooth muscle cell response to other growth factors. The Sm-like peptide will be further purified and its physicochemical properties determined. Since the Sm-like peptide is secreted and then rebinds as cell surface receptor, the factors that regulate Sm-C cell surface receptor concentration will be analyzed. The effect of a recently identified peptide that is secreted by fibroblasts on 125I-Sm-C binding to the smooth muscle cell surface will be determined. This factor will be purified and studies will be initiated to determine if it enhances the biologic response to Sm-C. Heparin is a potent inhibitor of smooth muscle cell growth. Since heparin alters the affinity of Sm-C for it's plasma binding protein, we will determine if it alters Sm-C binding to smooth muscle cells or the cellular DNA synthesis response to Sm-C. The effects of two recently discovered platelet derived mitogens on endothelial replication will be analyzed. Both factors will be purified to homogeneity and their chemical structures determined. The effects of pure mitogens on the endothelial cell response to peptide growth factors will be determined. The factors that mediate the release of these mitogens from platelets will be studied. Since two specific nucleotides are mitogens for endothelium, the capacity of these two nucleotides to be transported across endothelium will be compared to smooth muscle cells (a non-responsive cell type). Platelets appear to release a peptide inhibitor that specifically inhibits the effects of the endothelial mitogens. This inhibitor will be purified and its effect on the induction of DNA synthesis by purified growth factors determined. The results of these studies should provide basic information that is necessary to construct valid hypotheses regarding the role of these growth factors in the development of atherosclerosis.
Showing the most recent 10 out of 17 publications
