Vascular remodeling in chronic pulmonary hypertension is thought to involve elaboration of mediators that stimulate cell proliferation and synthesis of matrix proteins in the pulmonary artery (PA). Little is known, however, about the processes which lead to regression of remodeling following lowering of PA pressure. We have observed surprisingly rapid retum to normal structure of the main PA following recovery from hypoxic pulmonary hypertension in the rat. We postulate that reduction in PA pressure stimulates proteases in the blood vessel wall to degrade cellular and extracellular matrix proteins, and that these processes are similar to those regulating the transition from fetal to adult PA structure in the neonate. This postulate win be tested in adult rats recovering from hypoxic pulmonary hypertension (10 and 30 day exposure to 10% 02), in neonatal rats and in isolated PA rings in which wall tension is abruptly reduced. Evidence suggests that the mast cells are a key effector cell in breakdown of collagen, and the role of mast cells in regression will be studied in mast cell deficient mice and mast cells in culture. We propose to identify the proteolytic pathways which degrade intracellular and extracellular matrix proteins as well as the tissue inhibitor of metalloprotease (TIMP) using biochemical and molecular biology approaches. We will also characterize an apparently vascular-specific elastase using molecular genetics methods, and determine the cellular sources of proteases using immunohistochemical and in situ hybridization techniques. The role of tumor necrosis factor alpha, interleukin-1 and a degranulating agent in stimulating synthesis or release of collagenase from cultured mast cells will be tested. We will identify specific proteases involved in degradation of proteins in isolated PA rings which are stimulated by abrupt reduction in wall tension. These experiments may show that PAs sense reduction in wall tension when blood pressure is lowered and """"""""involute"""""""" by activation of proteases derived from specific cells in the PA wall. These studies may lead to new pathogenetic concepts about pulmonary vascular remodeling which may be pertinent to chronic pulmonary hypertension.
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