Prostaglandin E ₂ 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 the maintenance of pulmonary microvasculature. Prostaglandin E ₂ (PGE ₂) actsona set of E-prostanoid (EP) receptors that activate multiple signal transduction pathways leading to downstream responses. We investigated the modulation by PGE ₂ of VEGF release by human lung fibroblasts. Human lung fibroblasts were cultured until reaching 90% confluence in tissue culture plates, after which the culture media were changed to serum-free Dulbecco's modified Eagle's medium, with or without PGE ₂, andwith specific agonists or antagonists for eachEP receptor. After 2 days, culturemediawereassayed for VEGF by ELISA. The results demonstrated that PGE ₂ and the EP2 agonist ONO-AE1- 259-01 significantly stimulated the release of VEGF in a concentration- dependent manner. Agonists for other EP receptors did not stimulate the release of VEGF. The stimulatory effect of PGE ₂ was blocked by the EP2 antagonist AH6809, but was not blocked by antagonists for other EP receptors. The protein kinase-A (PKA) inhibitor KT-5720 also blocked the stimulatory effect of PGE ₂. The increased release of VEGF induced by PGE ₂ was accompanied by a transient increase in the concentration of VEGF mRNA. These findings demonstrate that PGE ₂ can modulate the release of VEGF by human lung fibroblasts through its actions in the EP2 receptor/ PKA pathway. This activity may contribute to the maintenance of pulmonary microvasculature in the alveolar wall.