Dataset Information

Estrogen receptor alpha isoform ERdelta7 in myometrium modulates uterine quiescence during pregnancy.

ABSTRACT:

Background

Circulating estrogen (E2) levels are high throughout pregnancy and increase towards term, however its local tissue specific actions vary across gestation. For example, myometrial E2 regulated uterotonic action is disabled until term, whereas it's proliferative function is maintained in the breast. We have identified gestationally regulated splicing events, mediated by hnRNPG and modulated by E2 that generate alternatively spliced estrogen receptor alpha (ER?) variants (ER?7 and ER?46) in the myometrium. These variants allow for differential, gestationally regulated, modulation of the uterotonic action of E2.

Methods

Human myometrium isolated from preterm and term non-laboring and laboring pregnant women were analyzed for ER? isoforms and splice factor levels. Lentiviral mediated shRNA knockdown of hnRNPG and overexpression of ER?7 were performed in human myometrial (hTERT-HM) cells. Functional 3D collagen contraction assays were executed.

Findings

ER?7 acts as a dominant negative repressor of the uterotonic action of ER?66 and ER?46 isoforms through the regulation of the myometrial gap junction protein GJA1. Elimination of hnRNPG inhibits the generation of ER?7 while overexpression of ER?7 inhibited GJA1 expression. Moreover in vivo human myometrial hnRNPG levels decline at term in an E2 dependent manner resulting in a withdrawal of ER?7 levels and its tocolytic action at term.

Interpretation

Our findings implicate the unique role of ER?7 as a modulator of myometrial quiescence and define the mechanism of ER?7 generation, through hormonally regulated splicing events. FUND: This study was supported by NIH OPRU U01 supplement (HD047905), University of Pittsburgh and Wayne State University Perinatal Research Initiative (USA).

SUBMITTER: Anamthathmakula P

PROVIDER: S-EPMC6355643 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Publications

Estrogen receptor alpha isoform ERdelta7 in myometrium modulates uterine quiescence during pregnancy.

Anamthathmakula Prashanth P Kyathanahalli Chandrashekara C Ingles Judith J Hassan Sonia S SS Condon Jennifer C JC Jeyasuria Pancharatnam P

EBioMedicine 20181128

<h4>Background</h4>Circulating estrogen (E2) levels are high throughout pregnancy and increase towards term, however its local tissue specific actions vary across gestation. For example, myometrial E2 regulated uterotonic action is disabled until term, whereas it's proliferative function is maintained in the breast. We have identified gestationally regulated splicing events, mediated by hnRNPG and modulated by E2 that generate alternatively spliced estrogen receptor alpha (ERα) variants (ERΔ7 an ...[more]

PMID: 30502052

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Project description:The pregnancy-augmented uterine vasodilation is linked to increased AT2R (angiotensin type-2 receptor) that mediates the vasodilatory effects of angiotensin II. However, the mechanisms controlling AT2R expression during pregnancy remain unclear. Estrogens are known to play a role in vascular adaptations during pregnancy. We hypothesized that estrogen stimulates uterine artery AT2R expression via ER (estrogen receptor)-?-dependent transcription in a pregnancy-specific endothelium-dependent manner. Plasma estradiol levels increased and peaked in late pregnancy and returned to prepregnant levels post-partum, correlating with uterine artery AT2R and ER? upregulation. Estradiol stimulated AT2R mRNA expression in endothelium-intact but not endothelium-denuded late pregnant and nonpregnant rat uterine artery ex vivo. Consistently, estradiol stimulated AT2R mRNA expression in late pregnant but not nonpregnant primary human uterine artery endothelial cells in vitro, which was abolished by ER antagonist ICI 182,780. Higher ER? protein bound to ER-responsive elements in AT2R promoter in the nonpregnant arteries whereas higher ER? bound in the pregnant state. ER? protein levels were similar but higher ER? protein levels were expressed in pregnant versus nonpregnant human uterine artery endothelial cells. Estradiol stimulation recruited ER? to the AT2R promoter in the nonpregnant state and ER? to the AT2R promoter in pregnancy; however, only ER? recruitment mediated transactivation of the AT2R reporter gene in pregnant human uterine artery endothelial cells. Estradiol-induced AT2R expression was abolished by the specific ER? (not ER?) antagonist 4-[2-Phenyl-5,7-bis(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-3-yl]phenol (PHTPP) and mimicked by the specific ER? (not ER?) agonist 2,3-bis(4-Hydroxyphenyl)-propionitrile (DPN) in pregnant human uterine artery endothelial cells in vitro. This study demonstrates a novel role of pregnancy-augmented ER? in AT2R upregulation in the uterine artery and provides new insights into the mechanisms underlying uterine vascular adaptation to pregnancy.

Dataset Information

Estrogen receptor alpha isoform ERdelta7 in myometrium modulates uterine quiescence during pregnancy.

Background

Methods

Findings

Interpretation

Publications

Estrogen receptor alpha isoform ERdelta7 in myometrium modulates uterine quiescence during pregnancy.

Similar Datasets

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