The proposed studies are planned to explore basic cellular mechanisms that may relate exposure to hypoxia to the development of pulmonary hypertension. It is hypothesized that hypoxia caused smooth muscle contraction either by direct effects on vascular smooth muscle or via alterations in endothelial cell metabolism. In previous studies we have found that exposure of bovine pulmonary artery endothelial cell sin culture to hypoxia/anoxia causes changes in transport and enzymatic activities of the endothelial cell membrane. These changes occur gradually and may reflect insidiously developing vascular tissue alterations that potentially result in increased vascular resistance. We now wish to further evaluate metabolic changes that occur in both endothelial and smooth muscle cells in culture exposed to hypoxia. Specifically, effects on serotonin transport, calcium fluxes, intracellular Ca2+ and cyclic nucleotides and possible interrelationships between these effects will be evaluated both independently and conjointly of the two cell types. Possible messages transmitted from the endothelial to the smooth muscle cell will be assessed by co-culture techniques and by testing products of endothelial cells exposed to hypoxia/anoxia on smooth muscle contraction in the isolated perfused lung, vascular ring preparations and smooth muscle cells in suspension. These products will also be tested for possible effects on smooth muscle Ca2+ metabolism and cyclic nucleotide concentrations. Observations of alterations of cellular function noted in cell culture will also be tested in intact vascular systems obtained from rats exposed to subatmospheric pressures in vivo. We hope that our approach will provide a more rational basis for understanding cellular mechanisms in the development of pulmonary hypertension.
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