Insulin-like growth factor I (IGF I) is a polypeptide that exerts marked effects on cellular proliferation and differentiation through both endocrine and autocrine/paracrine mechanisms. It is of major importance in developmental growth and possibly in abnormal growth responses. The proposed research program focuses on the regulation production of IGF I in the cardiovascular system. Cultured vascular smooth muscle, endothelial and cardiac cells, as well as several in vivo models will be used. Levels of IGF I will be determined by radioimmunoassay and by study of gene expression using [32p] IGF I cDNA and 'antisense' RNA probes.
Specific aims will include: 1) study of the conditions modulating IGF I secretion by cultured cells - in particular growth state, exposure to the growth factors PDGF, FGF, and human GH and the effects of mechanical forces such as shear stress, pressure and stretch 2) determination of the role of IGF I in a model of pressure-overload cardiac hypertrophy 3) characterization of IGF I binding to and growth-promoting effects on cultured heart cells 4) defining the role of vessel-wall production of IGF I in the proliferative response seen with increasing vascular load and with mechanically induced endothelial injury. These studies should provide important information on regulation of IGF I production by vascular cells and on the autocrine-paracrine function of IGF I, in particular its involvement in cardiac hypertrophy and the relation between IGF I production and the response of the vessel wall to mechanical stress. This research should provide major insights into the altered growth state present in disease states such as atherosclerosis, hypertension and cardiac hypertrophy.
