The proposed research focuses on hypoxic pulmonary hypertension and the pathogenic role of polyamines, a family of low molecular weight organic cations with documented intracellular regulatory roles in cell growth and differentation. Although pathologic and hemodynamic alterations characterizing hypertensive pulmonary vascular disease have been extensively studied, relatively little is known of the biochemical mechanisms regulating hyperplastic and hypertrophic responses the cells affecting the adverse vascular remodeling. The research proposed herein will test key elements of the working hypothesis that polyamines subserve an obligatory intracellular coupling role by linking exposure to chronic alveolar hypoxia with hyperplastic and hypertrophic responses of effector cells underlying development of hypertensive pulmonary vascular disease. Using intact rats chronically exposed to hypobaric hypoxia, studies are proposed to: 1) characterize the time- dependent effects of hypoxic exposure on lung polyamine biosynthesis; 2) determine if inhibition of polyamine biosynthesis forestalls progression of hypoxic pulmonary hypertension; and 3) immunocytochemically identify lung cell types in which chronic hypoxia enhances the content of the rate limiting enzyme in polyamine biosynthesis. Experiments in cultured pulmonary vascular endothelial cells, medial arterial smooth muscle cells and advential fibroblasts are proposed to: 5) determine at the cellular level if hypoxia-induced elaboration of mitogenic and differentiation factors are polyamine-dependent; and 6) determine if the actions of these factors on target cell populations are similarly polyamine-dependent. These studies will permit a rigorous evaluation of the role of polyamines as intracellular mediators coupling hypoxia to responses of pulmonary arterial effector cells implicated in hypertensive pulmonary vascular disease.
