ESTROGEN UP-REGULATES CYCLOOXYGENASE-1 GENE-EXPRESSION IN-OVINE FETALPULMONARY-ARTERY ENDOTHELIUM

Prostacyclin (PGI(2)) is a key mediator of pulmonary vasodilation in t he perinatal period and its synthesis in the pulmonary vasculature inc reases markedly during late gestation due to enhanced expression of th e rate-limiting enzyme cyclooxygenase-l (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 PGI(2) synth esis in nonpulmonary vascular cells, We therefore studied the direct e ffects of estrogen on COX-1 expression in ovine fetal pulmonary artery endothelial cells (PAEC), Exposure to estradiol-17 beta (E(2)beta, 10 (-10) to 10(-6) M) caused a dose-related increase in COX-1 mRNA expres sion that was evident after 48 h and maximal at 10(-8) M (fourfold inc rease). COX-1 mRNA stability was unchanged, suggesting that the upregu lation is mediated at the level of transcription. E(2)beta treatment ( 10(-8) M for 48 h) also caused a threefold increase in COX-1 protein e xpression and a threefold increase in PGI2 synthesis stimulated by bra dykinin, the calcium ionophore A23187, or arachidonic acid. The estrog en receptor (ER) antagonist ICI 182,780 fully reversed the effects of the hormone on COX-1 protein expression and on arachidonic acid-stimul ated PGI(2) synthesis, and ER expression was evident in the PAEC by im munoblot analysis. These findings indicate that physiologic levels of estrogen cause upregulation of COX-1 expression and PGI(2) synthesis i n fetal PAEC via activation of PAEC ER, This process may play a critic al role in optimizing the capacity for PGI(2)-mediated pulmonary vasod ilation at birth, and it may also be involved in estrogen responsivene ss in other vascular beds.