The major objective of this proposal is to study mechanisms controlling vascular smooth muscle cell (VSMC) growth in hypertension, with a specific focus on insulin-like growth factor I (IGF I). Adaptive growth of blood vessels in hypertension plays an inherent role in the pathology and morbidity/mortality of the disease. Structural changes in the resistance vasculature may contribute to the maintenance of hypertension. The renin- angiotensin system (RAS) is important in the control of blood pressure, and angiotensin ll is also a growth factor for VSMC. We have shown that the growth-promoting effects of angiotensin ll in vitro are mediated largely by the autocrine effects of IGF I. Furthermore, in high-renin hypertension in the rat (abdominal aortic coarctation), there is an induction of IGF I in the hypertensive vasculature. This is accompanied by an induction of one of the insulin-like growth factor binding proteins (IGFBPs), namely IGFBP-4, and by downregulation of the insulin-like growth factor I receptor (IGF IR). To dissect mechanisms important in regulation of the vascular IGF I system, we will: 1) study aortic coarctation hypertension in the rat and determine effects of blood pressure manipulation with and without blockade of the RAS, on IGF I, IGF IR, IGFBPs, and vascular growth responses; 2) Determine whether hypertension regulates IGF I independently of the RAS, by using the Dahl salt-sensitive (SS/Jr) rat; 3) determine whether angiotensin II infused at subpressor doses induces IGF I expression in the vasculature, and whether this induction correlates with development of medial hypertrophy; 4) determine whether the hypertrophic/hyperplastic effects of angiotensin H on the vasculature, and whether the slow pressor response to angiotensin II, are inhibited in a murine model in which the IGF I gene has been rendered non- functional by targeted homologous recombination (IGF I (-/-) mouse). In this mouse co-infusion of IGF I with angiotensin II should restore growth- promoting and slow pressor effects of angiotensin II. hi vivo studies will include characterization of circulating and vascular IGF I, IGF IR and IGFBPs. Conduit (elastic) and resistance (muscular) arteries will be studied. Methodologies to be used include northern and solution hybridization/RNase protection assays, in situ hybridization, immunohistochemistry, western blotting and western ligand blotting, radioimmunoassays, radioligand binding assays, PCR analysis, cross-linking studies, and morphometry. A homozygous IGF I (-/-) mouse colony will be established. These studies are critical to obtain an understanding of the function of the IGF I/IGF IR autocrine system in the vasculature and its regulation in hypertension. These studies will form the basis for the development of rational approaches to prevent vascular complications of hypertension.
| Mitch, W E; Bailey, J L; Wang, X et al. (1999) Evaluation of signals activating ubiquitin-proteasome proteolysis in a model of muscle wasting. Am J Physiol 276:C1132-8 |
