%0 Journal Article
%T Effects of the Catechol and Methoxy Metabolites of 17¦Â
%A Mayra B. Pastore
%A Ronald R. Magness
%A Rosalina Villalon Landeros
%J Reproductive Sciences
%@ 1933-7205
%D 2019
%R 10.1177/1933719118783265
%X 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¦Â, 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¦Â metabolites stimulate prostacyclin production in pregnancy-derived ovine uterine artery endothelial cells (P-UAECs); however, it is unknown whether the E2¦Â metabolites also induce NO production. Herein, UAECs derived from nonpregnant and pregnant ewes were used to test the hypothesis that E2¦Â 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¦Â metabolite-induced NO production. E2¦Â and its metabolites increased total nitric oxide metabolites (NOx) levels (NO2 + NO3) in P-UAECs, but not in NP-UAECs. Pretreatment with combined 1 ¦Ìmol/L 1,3-bis(4-hydroxyphenyl)-4-methyl-5-[4-(2-piperidinylethoxy)phenol]-1H-pyrazole dihydrochloride (MPP; ER-¦Á antagonist) and 1 ¦Ìmol/L 4-[2-phenyl-5,7-bis(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl]phenol (PHTPP; ER-¦Â antagonist) inhibited the rises in NOx levels stimulated by E2¦Â and 2-ME2, but had no effect on 2-OHE2-, 4-OHE2-, or 4-ME2-stimulated rises in NOx levels. Pretreatment with yohimbine (¦Á2-AR antagonist) and propranolol (¦Â2,3-AR antagonist) inhibited the rises in NOx levels stimulated by 2-OHE2, but not by E2¦Â, 4-OHE2, 2-ME2, or 4-ME2. These data demonstrate that E2¦Â 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
%K estrogen metabolites
%K endothelium
%K nitric oxide
%K adrenergic receptors
%K pregnancy
%U https://journals.sagepub.com/doi/full/10.1177/1933719118783265