I have been working on a guinea pig model of hypoxic pulmonary hypertension. We have found that significant chronic pulmonary hypertension and vascular remodeling associated with smooth muscle hyperplasia occurs in this model. In addition, thrombocytopenia is present and is probably due to platelet adherence to the pulmonary vasculature. The pulmonary hypertension, vascular remodeling, and thrombocytopenia are all partially prevented by treatment with heparin. These observations coupled with other data in the literature suggest that smooth muscle cell hyperplasia and platelet adhesion may be due to cellular changes of the endothelium induced by hypoxia. Heparin may interfere with these alterations by currently unknown mechanisms. On one hand, endothelial derived mitogen for smooth muscle proliferation has been described, and on the other hand it has been observed that heparin-like material derived from endothelium inhibits smooth muscle proliferation. Heparan sulfate is depressed in endothelial cells exposed to hypoxia, suggesting that this glycosaminoglycan may regulate smooth muscle proliferation produced by hypoxia. I plan in the proposed studies to 1) explore co-cultures of cells to evaluate the effects of hypoxia on endothelial cell/smooth muscle cell interaction and on smooth muscle and fibroblast proliferation and determine if heparin influences these processes in vitro; 2) assess possible mitogens produced by endothelial cells; 3) evaluate synthesis of heparan sulfate by the endothelial cell as a possible regulator of smooth muscle and fibroblast proliferation; 4) assess the influence of hypoxia on endothelial cell adherence properties for thrombin and platelets and evaluate the effect of heparin on adherence; and 5) evaluate the influence of hypoxia on endothelial and smooth muscle Ca2+ and cyclic nucleotide metabolism as possible messengers for proliferative changes produced by hypoxia.
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