PROSTAGLANDINS INDUCE VASCULAR ENDOTHELIAL GROWTH-FACTOR IN A HUMAN MONOCYTIC CELL-LINE AND RAT LUNGS VIA CAMP

Prostaglandins have emerged as a therapeutic option for patients with peripheral vascular disease as well as pulmonary hypertension as a mea ns to increase blood flow. We tested the hypothesis that prostaglandin s regulate vascular endothelial growth factor (VEGF) expression in the human monocytic THP-1 cell line and in isolated perfused rat lungs, O ur data show that the stable PGI(2)-analogue iloprost induces VEGF gen e expression (predorminantly VEGF(121), but also VEGF(165) isoforms) a nd VEGF protein synthesis in THP-1 cells, This effect is abolished by dexamethasone and by Rp-cAMP, a specific inhibitor of cAMP-dependent p rotein kinase (PKA) activation. The calcium channel blocker diltiazem has no effect on the iloprost-induced VEGF gene expression, and deplet ion of intracellular Ca2+ stores by long-term exposure (16 h) of THP-1 cells to thapsigargin does not inhibit iloprost-induced VEGF gene exp ression, suggesting that an increase in intracellular Ca2+ is not esse ntial for VEGF gene induction by iloprost. However, an increase of int racellular Ca2+ by a short-term (2 h) exposure of THP-1 cells to thaps igargin or to the calcium-ionophore A23187 increases VEGF mRNA levels, indicating that a change in intracellular Ca2+ by itself can alter VE GF gene expression. The effects of thapsigargin or A23187 on VEGF gene expression are also mediated via cAMP-PKA since they are inhibited by Rp-cAMP. In isolated perfused rat lungs, PGI(2) and PGE(2) increases VEGF mRNA abundance whereas Rp-cAMP inhibits the prostaglandin-induced VEGF gene activation. Thus, our data suggest that prostaglandins stim ulate VEGF gene expression in monocytic cells and in rat lungs via a c AMP-dependent mechanism.