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

Abstract

Prostacyclin (PGI 2 ) 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 PGI 2 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-17 ␤ (E 2 ␤ , 10 Ϫ 10 to 10 Ϫ 6 M) caused a dose-related increase in COX-1 mRNA expression that was evident after 48 h and maximal at 10 Ϫ 8 M (fourfold increase). COX-1 mRNA stability was unchanged, suggesting that the upregulation is mediated at the level of transcription. E 2 ␤ treatment (10 Ϫ 8 M for 48 h) also caused a threefold increase in COX-1 protein expression and a threefold increase in PGI 2 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 PGI 2 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 PGI 2 synthesis in fetal PAEC via activation of PAEC ER. This process may play a critical role in optimizing the capacity for PGI 2 -mediated pulmonary vasodilation at birth, and it may also be involved in estrogen responsiveness in other vascular beds. ( J.

Characteristics of contractile activity in the renal artery of ovariectomized rats

“…Studies have shown that estrogen may regulate vascular tone in the cerebral artery by shifting cyclooxygenase-1 (COX-1)-dependent vasodilatation or vasoconstriction (Ospina et al, 2003;Jun et al, 1998). Indomethacine significantly, albeit slightly, affected contractile responses to PE in the current investigation; however, no differences were detected among the three groups (data not shown).…”

Elevated mean arterial pressure in the ovariectomized rat was normalized by ETA receptor antagonist therapy: absence of cardiac hypertrophy and fibrosis

“…Several studies have demonstrated that oestrogen stimulated the synthesis and release of the vasodilator/antiproliferative factor nitric oxide via both a genomic and non-genomic mechanism acting at the level of nitric oxide synthase (Kim et al, 1999;Kleinert et al, 1998). Secondly, oestrogen increased the synthesis of the potent vasodilator prostacylin via a non-genomic action in endothelial cells (Jun et al, 1998). Concomitant with the increased synthesis of vasodilatory factors, oestrogen treatment of endothelial cells inhibited the expression of the potent vasoconstrictor/proliferative peptide endothelin-1 (Morey et al, 1998).…”

“…Nitric oxide is a potent vasodilator of the underlying vasculature, and an important antiproliferative factor (Lloyd-Jones & Bloch, 1996;Garg & Hassid, 1989). Secondly, oestrogen treatment of endothelial cells increased the synthesis of the vasodilator prostacyclin via a non-genomic mechanism (Jun et al, 1998). Thirdly, in vivo studies have demonstrated that oestrogen inhibited adverse vascular smooth cell remodelling (Chen et al, 1996).…”

Estrogens and atherosclerosis: insights from animal models and cell systems

“…Another vasorelaxing substance liberated from endothelial cells under the influence of E 2 is prostacyclin (PGI 2 ; Mikkola et al 1995, Seeger et al 1999, Sherman et al 2002. The latter effect depends on the combined increased synthesis of cyclooxygenase 1 and/or 2 (COX1 (PTGS1) and COX2 (PTGS2)) and prostaglandin synthase (PGH 2 ), which ultimately leads to a shift from COX-dependent vasoconstriction to vasodilation (Jun et al 1998, Akarasereenont et al 2000, Kawagoe et al 2007, Sobrino et al 2009). Experiments with ER agonists and endothelial cells transfected with COX promoter suggest the involvement of both ERa and ERb in E 2 -dependent PGI 2 production (Gibson et al 2005, Sobrino et al 2010, albeit 2-ME was also demonstrated to enhance PGI 2 liberation (Barchiesi et al 2006).…”