VASCULAR CELL PHENOTYPES IN PULMONARY HYPERTENSION

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DESCRIPTION: (Adapted from the applicant's abstract and Specific Aims.) The walls of injured blood vessels rapidly thicken in pulmonary hypertension (PH), especially those of the microvessels, where lumen restriction increases pulmonary vascular resistance and pressure. As cell hypertrophy and proliferation narrow the vessel lumen, cell and matrix components are organized into new intimal, medial, and adventitial layers, and new contractile cells develop in normally nonmuscular segments (i.e., neomuscularization). The expression of filament proteins responsible for the vascular cell differentiation that accompanies this pattern of growth remain uncharacterized. Results show that intermediate cells and migrating interstitial fibroblasts recruited to the injured vessel wall form first intimal and then medial cell layers; structurally, they acquire microfilaments and organelles associated with contraction, but only in some is myosin preferentially expressed. Tropoelastin synthesis by these cells, and elastic lamina(e) formation, are critical to their organization within the vessel wall. The application proposes that there is regional and differential regulation of smooth muscle myosin in the cells of the microvascular segments in PH. The hypothesis is that during wall remodeling, cells of the intermediate pathway rapidly increase myosin expression while those of the fibroblast pathway increase expressionof cytoskeletal proteins. The Specific Aims are to: 1) identify the distribution of filament proteins, by analyzing the expression of actin microfilaments, intermediate filaments, and myofilaments by high resolution immunocytochemistry; 2) define the cell lattice by the subcellular distribution of filaments and organelles by high resolution microscopy; 3) establish regulation of myosin and tropoelastin mRNA expression by in situ hybridization; and 4) establish the effects of the challenge of relative hypoxia on the "hyperoxia-adapted and weaned lung" by return to breathing air. By defining the organization and type of contractile and cytoskeletal filaments, the goal is to understand the phenotypic switching that occurs in the cells of specific vascular segments as they remodel the vascular wall in PH.