Effects of the Catechol and Methoxy Metabolites of 17β-Estradiol on Nitric Oxide Production by Ovine Uterine Artery Endothelial Cells. (April 2019)

• Record Type: Journal Article
• Authors: Landeros, Rosalina Villalon; Pastore, Mayra B.; Magness, Ronald R.
• Is Part Of: Reproductive sciences. Volume 26:Number 4(2019:Apr.)
• Page Start: 459
• Page End: 468
• Publication Date: 2019-04
• Subjects: estrogen metabolites -- endothelium -- nitric oxide -- adrenergic receptors -- pregnancy; Reproductive health -- Periodicals; Reproduction -- Periodicals; 612.6
• DOI: 10.1177/1933719118783265
• Languages: English
• ISSNs: 1933-7191

Abstract

Nitric oxide (NO) production is essential to facilitate rises in uterine blood flow (UBF) during pregnancy. It has been proposed that the metabolites of E2 β, 2-hydroxyestradiol (2-OHE2 ), 4-hydroxyestradiol (4-OHE2 ), 2-methoxyestradiol (2-ME2 ), and 4-methoxyestradiol (4-ME2 ) play a role in mediating vasodilation and rises in UBF during pregnancy. We previously showed that the E2 β metabolites stimulate prostacyclin production in pregnancy-derived ovine uterine artery endothelial cells (P-UAECs); however, it is unknown whether the E2 β metabolites also induce NO production. Herein, UAECs derived from nonpregnant and pregnant ewes were used to test the hypothesis that E2 β metabolites stimulate NO production in a pregnancy-specific manner. Specific estrogen receptor (ER) and adrenergic receptor (AR) antagonists were used to determine the roles of ERs or ARs in E2 β metabolite-induced NO production. E2 β and its metabolites increased total nitric oxide metabolites (NOx) levels (NO2 + NO3 ) in P-UAECs, but not in NP-UAECs. Pretreatment with combined 1 µmol/L 1, 3-bis(4-hydroxyphenyl)-4-methyl-5-[4-(2-piperidinylethoxy)phenol]-1H-pyrazole dihydrochloride (MPP; ER-α antagonist) and 1 µmol/L 4-[2-phenyl-5, 7-bis(trifluoromethyl)pyrazolo[1, 5-a]pyrimidin-3-yl]phenol (PHTPP; ER-β antagonist) inhibited the rises in NOx levels stimulated by E2 β and 2-ME2, but had no effect on 2-OHE2 -, 4-OHE2 -, or 4-ME2 -stimulated rises in NOx levels. Pretreatment with yohimbine (α2 -AR antagonist) and propranolol (β2, 3 -AR antagonist) inhibited the rises in NOx levels stimulated by 2-OHE2, but not by E2 β, 4-OHE2, 2-ME2, or 4-ME2 . These data demonstrate that E2 β metabolites stimulate NO synthesis via ERs or ARs in UAECs in a pregnancy-specific manner, suggesting that these metabolites contribute to rises in vasodilation and UBF during pregnancy.