Although much is known about the pathology of pulmonary hypertension, only sparse information is available regarding signalling mechanisms which orchestrate lung cell responses driving adverse changes in pulmonary vascular structure. One important transduction pathway involves the polyamines, a family of low molecular weight organic cations that are essential for DNA, RNA, and protein synthesis. Because changes in lung cell polyamine contents may comprise a unified pathway through which diverse stimuli affect hypertensive pulmonary vascular remodeling, mechanisms regulating cellular polyamine contents may offer unique opportunities for pharmacologic intervention. Increased activity of ornithine decarboxylase (ODC), the initial rate-limiting enzyme in de novo polyamine synthesis, is necessary for postnatal lung development and for structural remodeling induced by pneumonectomy, hyperoxia, and monocrotaline. In marked contrast, ODC activity is profoundly decreased in hypoxic pulmonary hypertension despite large increases in lung polyamine contents. Mechanisms regulating lung polyamines in hypoxia thus seem to differ fundamentally from other conditions so far studied. The proposed research will test key aspects of the working hypothesis that chronic hypoxia increases lung polyamine contents through induction of transmembrane polyamine transport in pulmonary arterial cells. Integrated studies conducted in intact rats, isolated rat lungs, and cultured rat main pulmonary artery smooth muscle cells and microvascular endothelial cells will: (1) Determine if chronic hypoxia engenders polyamine transport by pulmonary arterial cells involved with hypertensive vascular remodeling and test the hypothesis that discrete polyamine transport pathways are differentially regulated by chronic hypoxia; (2) Characterize polyamine transport in cultured pulmonary artery smooth muscle and endothelial cells and examine mechanisms by which chronic hypoxia depresses ODC activity and increases polyamine transport; and (3) Delineate mechanisms governing interaction between transported polyamines and polyamine metabolizing enzymes. This research will provide basic information on mechanisms regulating lung cell polyamine contents and determine how these processes are modified in the setting of chronic hypoxic pulmonary hypertension. Identification of augmented transmembrane polyamine transport as a major determinant of lung cell polyamine contents in chronic hypoxia is directly responsive to the need for development of selective pharmacologic interventions in this and similar disorders.
