Hypoxia enhances cellular proliferation and inositol 1,4,5-triphosphate generation in fibroblasts from bovine pulmonary artery but not from mesenteric artery

When pulmonary hypertension occurs in the face of hypoxia there is remodeli ng of all three layers of the pulmonary vessels, but in particular, there i s an increase in number of adventitial fibroblasts. Hypoxia causes vasocons triction in the pulmonary circulation and vasodilation in the systemic circ ulation. We hypothesized that there are fundamental differences in oxygen s ensing and cell signaling between systemic and pulmonary artery cells in re sponse to hypoxia. Here, we determined the effect of hypoxia either alone o r in combination with known growth factors such as serum, endothelin-l (ET- 1), and platelet-derived growth factor (PDGF) on the proliferative response s of bovine pulmonary artery and mesenteric artery fibroblasts. Fibroblasts were obtained from primary cultures. Growth was assessed by [H-3]thymidine incorporation. Inositol 1,4,5-triphosphate (IP,) generation was measured u sing a competitive binding assay. Hypoxia alone increased proliferation of pulmonary artery fibroblasts (611 +/- 24%), but not in those from the mesen tery. Furthermore, hypoxia had the effect of increasing the replicative res ponse of pulmonary fibroblasts to serum and PDGF, but no change was observe d in the mesenteric cells. ET-1 had no effect on growth of either cell type . PDGF gave rise to a significant elevation in IF, production under hypoxic conditions in the pulmonary artery cells (234%), but not in the mesenteric cells. ET-1 caused no change in IP3 production in any cell type. These dat a suggest that hypoxia sensitizes pulmonary artery fibroblasts to the proli ferative effect of mitogens through a pathway that is not present, or is pr esent but repressed, in the mesenteric cells.