Convergent ERK1/2, p38 and JNK mitogen activated protein kinases (MAPKs) signalling mediate catecholoestradiol-induced proliferation of ovine uterine artery endothelial cells.

Key Points: The catechol metabolites of 17β-oestradiol (E β), 2-hydroxyoestradiol (2-OHE ) and 4-hydroxyoestradiol (4-OHE ), stimulate proliferation of pregnancy-derived ovine uterine artery endothelial cells (P-UAECs) through β-adrenoceptors (β-ARs) and independently of the classic oestrogen receptors (ERs). Herein we show that activation of ERK1/2, p38 and JNK mitogen activated protein kinases (MAPKs) is necessary for 2-OHE - and 4-OHE -induced P-UAEC proliferation, as well as proliferation induced by the parent hormone E β and other β-AR signalling hormones (i.e.

Estradiol 17β and its metabolites stimulate cell proliferation and antagonize ascorbic acid-suppressed cell proliferation in human ovarian cancer cells.

Estradiol 17β (E2β) and ascorbic acid (AA) have been implicated in cancer progression. However, little is known about the actions of biologically active metabolites of E2β, 2-hydroxyestradiol (2OHE2), 4-hydroxyestradiol (4OHE2), 2-methoxyestradiol (2ME2), and 4-methoxyestradiol (4ME2) synthesized sequentially by cytochrome P450, family 1, subfamily A (CYP1A1) and B (CYP1B1), polypeptide 1, and catechol-O-methyltransferase (COMT) on ovarian cancer. Herein, we examined the expression of CYP1A1, CYP1B1, COMT, and estrogen receptor α (ERα) and β (ERβ) in human ovarian surface epithelial (IOSE-385) and cancer cell lines (OVCAR-3, SKOV-3, and OVCA-432).

Estradiol-17β and its cytochrome P450- and catechol-O-methyltransferase-derived metabolites selectively stimulate production of prostacyclin in uterine artery endothelial cells: role of estrogen receptor-α versus estrogen receptor-β.

Metabolism of estradiol-17β to 2-hydroxyestradiol, 4-hydroxyestradiol, 2-methoxyestradiol, and 4-methoxyestradiol contributes importantly to the vascular effects of estradiol-17β in several vascular beds. However, little is known about the role of estradiol-17β metabolites via the different estrogen receptors (ER-α/ER-β) on de novo endothelial prostacyclin and thromboxane production. We hypothesized that estradiol-17β and its metabolites, via ER-α or ER-β, can enhance the prostacyclin/thromboxane ratio through the classic phospholipase A(2), cyclooxygenase-1, and prostacyclin synthase pathway in ovine uterine artery endothelial cells (UAECs) derived from pregnant (P-UAECs) versus nonpregnant (NP-UAECs) ewes.

Aberrant synthesis, metabolism, and plasma accumulation of circulating estrogens and estrogen metabolites in preeclampsia implications for vascular dysfunction.

Estrogens and estrogen metabolites have important functions in cardiovascular and other physiology, yet the patterns of estrogen synthesis, metabolism, and the individual plasma profile of estrogens and estrogen metabolites during human pregnancy as well as in preeclampsia remain undetermined. We performed liquid chromatography mass spectrometry on plasma samples from normotensive pregnant women (normP; n=8), women with mild (mPE; n=8), and severe (sPE; n = 8) preeclampsia at labor. Compared with normP, estrone was lower in sPE, whereas plasma level of estradiol-17β was significantly lower in women with mPE and sPE.

Estrogen receptor-α and estrogen receptor-β in the uterine vascular endothelium during pregnancy: functional implications for regulating uterine blood flow.

The steroid hormone estrogen and its classical estrogen receptors (ERs), ER-α and ER-β, have been shown to be partly responsible for the short- and long-term uterine endothelial adaptations during pregnancy. The ER-subtype molecular and structural differences coupled with the differential effects of estrogen in target cells and tissues suggest a substantial functional heterogeneity of the ERs in estrogen signaling. In this review we discuss (1) the role of estrogen and ERs in cardiovascular adaptations during pregnancy, (2) in vivo and in vitro expression of ERs in uterine artery endothelium during the ovarian cycle and pregnancy, contrasting reproductive and nonreproductive arterial endothelia, (3) the structural basis for functional diversity of the ERs and estrogen subtype selectivity, (4) the role of estrogen and ERs on genomic responses of uterine artery endothelial cells, and (5) the role of estrogen and ERs on nongenomic responses in uterine artery endothelia.

A novel role for an endothelial adrenergic receptor system in mediating catecholestradiol-induced proliferation of uterine artery endothelial cells.

Sequential conversion of estradiol-17β to its biologically active catecholestradiols, 2-hydroxyestradiol (OHE(2)) and 4-OHE(2), contributes importantly to its angiogenic effects on uterine artery endothelial cells (UAECs) derived from pregnant, but not nonpregnant ewes via an estrogen receptor-independent mechanism. Because catecholestradiols and catecholamines exhibit structural similarities and have high affinity for α- and β-adrenergic receptors (ARs), we investigated whether the endothelial α- or β-ARs mediate catecholestradiol-induced proliferation of P-UAECs and whether catecholamines alter these responses. Western analyses revealed expression of specific AR subtypes in nonpregnant UAECs and P-UAECs, including α(2)-, β(2)-, and β(3)-ARs but not α(1)- and β(1)-ARs.

Alcohol and maternal uterine vascular adaptations during pregnancy-part I: effects of chronic in vitro binge-like alcohol on uterine endothelial nitric oxide system and function.

Background: Pregnancy-induced utero-placental growth, angiogenic remodeling, and enhanced vasodilation are all partly regulated by estradiol-17β-mediated activation of endothelial nitric oxide synthase (eNOS) and nitric oxide (NO) production. However, very little is known about the effects of alcohol on these maternal utero-placental vascular adaptations during pregnancy and its potential role in the pathogenesis of fetal alcohol spectrum disorders (FASDs). In this study, we hypothesized that in vitro chronic binge-like alcohol will decrease uterine arterial endothelial eNOS expression and alter its multisite phosphorylation activity state via disruption of AKT signaling.

Estradiol-17beta and its cytochrome P450- and catechol-O-methyltransferase-derived metabolites stimulate proliferation in uterine artery endothelial cells: role of estrogen receptor-alpha versus estrogen receptor-beta.

Estradiol-17beta (E(2)beta) and its metabolites, which are sequentially synthesized by cytochrome P450s and catechol-O-methyltransferase to form 2 and 4-hydroxyestradiol (OHE(2)) and 2- and 4-methoxestradiol (ME(2)), are elevated during pregnancy. We investigated whether cytochrome P450s and catechol-O-methyltransferase are expressed in uterine artery endothelial cells (UAECs) and whether E(2)beta and its metabolites modulate cell proliferation via ER-alpha and/or ER-beta and play roles in physiological uterine angiogenesis during pregnancy. Cultured ovine UAECs from pregnant and nonpregnant ewes were treated with 0.