Hypoxia enhances cellular proliferation and inositol 1,4,5-triphosphate generation in fibroblasts from bovine pulmonary artery but not from mesenteric artery
Dj. Welsh et al., Hypoxia enhances cellular proliferation and inositol 1,4,5-triphosphate generation in fibroblasts from bovine pulmonary artery but not from mesenteric artery, AM J R CRIT, 158(6), 1998, pp. 1757-1762
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.