The hypoxic pulmonary vasoconstrictor response is a phenomenon of enormous physiologic and pathologic significance whose mechanism is not understood. The essential elements of the response are known to be contained within the pulmonary parenchyma. Much investigation has focused upon certain chemical mediators which, if synthesized within the lung in response to hypoxia, could act upon vascular smooth muscle cells to induce contraction. The sponsor's laboratory has provided evidence that the expression of platelet derived growth factor (PDGF) and endothelin-1, both potent vasoconstrictors, can be induced by hypoxia in endothelial cells. It is known that PDGF and endothelin can be produced by smooth muscle cells as well. We hypothesize that hypoxic induction of PDGF and endothelin occurs in vascular smooth muscle cells, allowing an autocrine level of regulation could be responsible for faster, more direct regulation of pulmonary vasoconstriction than might be expected from endothelial cell mediators, and might account for the rapid response to hypoxia observed in vivo. Recent work has also produced evidence that there exists an oxygen-sensitive heme protein which detects hypoxia in the endothelial cell, and which presumably is responsible for transducing the signal required for induction of PDGF and endothelin-1. Identification of such a molecule would be an important accomplishment, potentially opening avenues for pharmacologic intervention in diseases involving pulmonary hypertension.
Our Specific Aims are: 1) Using standard techniques of molecular biology, to determine whether hypoxia regulates expression of PDGF and ET-1 in smooth muscle cells as it does in endothelial cells; 2) To assess smooth muscle cells for oxygen sensing ability, as demonstrated by the capacity to regulate expression from a transfected oxygen-responsive promoter; 3) To isolate the oxygen sensing protein or its gene in endothelial cells by expression cloning, anti- porphyrin antibodies, or iron labeling.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Physician Scientist Award (K11)
Project #
5K11HL002879-03
Application #
2210718
Study Section
Special Emphasis Panel (NSS)
Project Start
1992-04-10
Project End
1995-04-06
Budget Start
1993-09-30
Budget End
1995-04-06
Support Year
3
Fiscal Year
1993
Total Cost
Indirect Cost
Name
Children's Hospital Boston
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115