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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37HL032723-05
Application #
3486045
Study Section
Respiratory and Applied Physiology Study Section (RAP)
Project Start
1984-07-01
Project End
1992-06-30
Budget Start
1988-07-01
Budget End
1989-06-30
Support Year
5
Fiscal Year
1988
Total Cost
Indirect Cost
Name
Tufts University
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02111
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Fanburg, B L; Lee, S L (2000) A role for the serotonin transporter in hypoxia-induced pulmonary hypertension. J Clin Invest 105:1521-3
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