HYPERTENSIVE PULMONARY VASCULAR REMODELING--ROLE OF IGF

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Research: The research proposed explores the mechanisms of vascular remodeling in chronically hypertensive pulmonary arteries (PA). Pulmonary hypertension is a serious disorder associated with significant morbidity and mortality. Chronic pulmonary hypertension associated with vascular remodeling is characterized by limited response to treatment with oxygen and vasodilators. Improved understanding of the remodeling process would hopefully lead to therapeutic interventions. This proposal examine the role of peptide growth factors in the cellular hyperplasia/hypertrophy and increased extracellular matrix (ECM) production characteristic of hypertensive pulmonary vascular remodeling. Studies will initially focus on insulin-like growth factor I (IGF-I), and later examine possible synergism with platelet-derived growth factor (PDGF) and transforming growth factor beta (TGF-B). Most of the experiments proposed will be carried out in vitro on cells isolated from the pulmonary arteries of neonatal calves, often under conditions simulating those which lead tot he development of chronic pulmonary hypertension in vivo (hypoxia, simulated hemodynamic stress). Considerable effort will be made to relate these in vitro studies to the neonatal calf model of severe chronic hypoxic pulmonary hypertension developed in this laboratory. Specific Aims will be to: 1) Characterize the effects of IGF-I on normal neonatal bovine PA smooth muscle cells (SMC) and fibroblasts with regard to cellular proliferation and ECM production, 2) Determine if IGF-I production and/or responsiveness by vascular wall cells are increased under conditions associated with the development of chronic hypoxic pulmonary hypertension, 3) Study possible synergism of PDGF and TGF-B with IGF-I with regard to cellular proliferation and ECM production, in the presence and absence of hypoxia and simulated hemodynamic stress. Environment: The pathogenesis of pulmonary hypertension is under intensive investigation in the Cardiovascular Pulmonary Research Laboratory at the University of Colorado in Denver. This is a large laboratory with many very well qualified clinical scientists, excellent equipment, facilities, and technical support, and a reputation for preparing researchers for successful careers as independent investigators. The large academically- oriented Pulmonary Division at the University of Colorado further enhances the environment for career development.