The proposed project will investigate the basic mechanism by which vascular smooth muscle proliferation is regulated. In this connection, experiments are designed to determine the mechanisms by which PDGF stimulates vascular smooth muscle growth as well as the role of PGI2 in this process. Since studies in other cell systems suggest that CA++ mediated Na+ fluxes are triggers for mitogenesis, the effect of PDGF on Ca++ and Na+ transport will be measured. Furthermore, PGI2 is known to have its pharmacological activity via elevations in cAMP levels. Since cAMP is inhibitory to growth in a variety of cell types, the relationship between cAMP levels and DNA synthesis will be determined in vascular smooth muscle cells. Finally, I will investigate the relationship between PDGF and PGI2/cAMP in modulation of vascular smooth muscle proliferation. It has been suggested that cAMP reduces intracellular Ca++ levels and experiments will be performed to examine this contention. This study by focusing on the underlying principles involved in vascular smooth muscle proliferation should provide valuable information relative to the future development of therapeutic agents useful in the treatment of atherosclerosis.
