Estrogen upregulates cyclooxygenase-1 gene expression in ovine fetal pulmonary artery endothelium

Prostacyclin (PGI₂) is a key mediator of pulmonary vasodilation in the perinatal period and its synthesis in the pulmonary vasculature increases markedly during late gestation due to enhanced expression of the rate- limiting enzyme cyclooxygenase-1 (COX-1). The hormone estrogen may play a role in COX-1 upregulation since fetal estrogen levels rise dramatically during late gestation and estrogen enhances PGI₂ synthesis in nonpulmonary vascular cells. We therefore studied the direct effects of estrogen on COX-1 expression in ovine fetal pulmonary artery endothelial cells (PAEC). Exposure to estradiol-17β (E₂β, 10^-10 to 10^-6 M) caused a dose-related increase in COX-1 mRNA expression that was evident after 48 h and maximal at 10^-8 M (fourfold increase). COX-1 mRNA stability was unchanged, suggesting that the upregulation is mediated at the level of transcription. E₂β treatment (10^-8 M for 48 h) also caused a threefold increase in COX-1 protein expression and a threefold increase in PGI₂ synthesis stimulated by bradykinin, the calcium ionophore A23187, or arachidonic acid. The estrogen receptor (ER) antagonist ICI 182,780 fully reversed the effects of the hormone on COX-1 protein expression and on arachidonic acid-stimulated PGI₂ synthesis, and ER expression was evident in the PAEC by immunoblot analysis. These findings indicate that physiologic levels of estrogen cause upregulation of COX-1 expression and PGI₂ synthesis in fetal PAEC via activation of PAEC ER. This process may play a critical role in optimizing the capacity for PGI₂-mediated pulmonary vasodilation at birth, and it may also be involved in estrogen responsiveness in other vascular beds.