Prostaglandin E2 stimulates the production of vascular endothelial growth factor through the E-prostanoid-2 receptor in cultured human lung fibroblasts

Fibroblasts are the major mesenchymal cells present within the interstitium of the lung and are a major source of vascular endothelial growth factor (VEGF), which modulates maintenance of the pulmonary microvasculature. Prostaglandin E2 (PGE2) acts on a set of E-prostanoid (EP) receptors that activate multiple signal transduction pathways leading to downstream responses. This study investigates PGE2 modulation of VEGF release by human lung fibroblasts. Human lung fibroblasts were cultured until 90% confluence in tissue culture plates, after which culture media were changed to serum-free DMEM with or without PGE2 and specific agonists and/or antagonists for each EP receptor. After 2 days, culture media were assayed for VEGF by ELISA. The results demonstrate that PGE2 and the EP2 agonist ONO-AE1-259-01 significantly stimulated VEGF release in a concentration-dependent manner. Agonists for other EP receptors did not stimulate VEGF release. The stimulatory effect of PGE2 was blocked by the EP2 antagonist AH6809 but was not blocked by the antagonists for other EP receptors. The protein kinase-A (PKA) inhibitor KT-5720 also blocked the stimulatory effect of PGE2. The increased release of VEGF induced by PGE2 was accompanied by a transient increase in VEGF mRNA level. The findings demonstrate that PGE2 can modulate VEGF release by human lung fibroblasts by acting on the EP2 receptor/PKA pathway. This activity could contribute to maintenance of pulmonary microvasculature in the alveolar wall