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-17beta (E2beta, 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. E2beta 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.
Jun
S S
SS
Department of Pediatrics, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75235-9063, USA.
Chen
Z
Z
Pace
M C
MC
Shaul
P W
PW
D000818:Animals; D002478:Cells, Cultured; D051545:Cyclooxygenase 1; D004730:Endothelium, Vascular / Q000201:enzymology*; D011464:Epoprostenol / Q000096:biosynthesis; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D007527:Isoenzymes / Q000235:genetics*; D011247:Pregnancy; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics*; D011651:Pulmonary Artery / Q000201:enzymology*; D011652:Pulmonary Circulation; D012333:RNA, Messenger / Q000032:analysis; D011960:Receptors, Estrogen / Q000502:physiology; D012756:Sheep; D015854:Up-Regulation
D004967:Estrogens; D007527:Isoenzymes; D012333:RNA, Messenger; D011960:Receptors, Estrogen; D011464:Epoprostenol; D051545:Cyclooxygenase 1; D011451:Prostaglandin-Endoperoxide Synthases