Insulin-Like Growth Factor I (IGF I) has marked effects on cellular proliferation and differentiation through both endocrine and autocrine/paracrine mechanisms. It is produced and secreted by vascular cells in vitro and exerts its effects after binding to a specific high- affinity membrane receptor. Platelet-derived growth factor (PDGF) may be released from aggregating platelets/monocytes at sites of endothelial injury/dysfunction as well as from vascular smooth muscle cells (VSMC) and modulates IGF I gene expression. The primary focus of this proposal is to study the role of IGF I and of its receptor in vascular growth responses to a variety of stimuli and to determine whether blocking the IGF I receptor alters vessel wall hypertrophy/hyperplasia.
Specific Aims will include: 1) Characterization of the regulation of IGF I gene expression in cultured vascular smooth muscle cells and in aorta by PDGF. 2) Analysis of IGF I receptor gene expression and binding in vitro and in vivo, its regulation by PDGF and its role in the remodeling of the arterial wall seen in aortic, coarctation hypertension in the rat and following balloon-injury of the rat aorta. 3) Development of specific blocking antibodies against the IGF I receptor to study their effects in vitro and to determine whether blocking IGF I binding in vivo in the rat alters the hypertrophic/ hyperplastic response of the arterial wall to increased blood pressure and attenuates the proliferative neointimal response to balloon-injury of the rat aorta. 4) Study ICF I and ICF I receptor gene expression in developing myocardial collateral arteries in the dog. This proposal directly addresses the role of IGF I and its receptor in growth of the arterial wall in response to increased blood pressure and following mechanical injury and will define molecular mechanisms whereby PDGF modulates gene expression of IGF I and its receptor. These issues are key to understanding the pathophysiology of the arterial remodeling present in hypertension and following balloon-injury and should provide major insights into the mechanisms regulating the growth of VSMC in disease states such as atherosclerosis. Defining the effect of IGF I receptor blockade should permit us to develop therapeutic approaches targeted toward specific clinical problems such as post-angioplasty restenosis and accelerated atherosclerosis.
Showing the most recent 10 out of 38 publications
