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

Abstract

BackgroundCirculating 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 and ERα46) in the myometrium. These variants allow for differential, gestationally regulated, modulation of the uterotonic action of E2.MethodsHuman myometrium isolated from preterm and term non-laboring and laboring pregnant women were analyzed for ERα isoforms and splice factor levels. Lentiviral mediated shRNA knockdown of hnRNPG and overexpression of ERΔ7 were performed in human myometrial (hTERT-HM) cells. Functional 3D collagen contraction assays were executed.FindingsERΔ7 acts as a dominant negative repressor of the uterotonic action of ERα66 and ERα46 isoforms through the regulation of the myometrial gap junction protein GJA1. Elimination of hnRNPG inhibits the generation of ERΔ7 while overexpression of ERΔ7 inhibited GJA1 expression. Moreover in vivo human myometrial hnRNPG levels decline at term in an E2 dependent manner resulting in a withdrawal of ERΔ7 levels and its tocolytic action at term.InterpretationOur findings implicate the unique role of ERΔ7 as a modulator of myometrial quiescence and define the mechanism of ERΔ7 generation, through hormonally regulated splicing events.FundThis study was supported by NIH OPRU U01 supplement (HD047905), University of Pittsburgh and Wayne State University Perinatal Research Initiative (USA).

Pathogenesis of preterm birth: bidirectional inflammation in mother and fetus

“…The decline in P4 signaling induces a switch of the myometrium from a quiescent to a contractile state at labor [127]. However, evidence places the establishment of myometrial quiescence also at the start of gestation, as it may be regulated by estrogen and P4 hormone receptor signaling [128]. Besides the myometrium, the endometrium and decidua are also proposed to be responsible for the timing of birth via induction of a decidual "clock."…”

Dynamic transcriptome, accessible genome, and PGR cistrome profiles in the human myometrium

“…[6][7][8][9][10] Estrogen modulates contraction-associated genes and induces hyperplasia of myometrial smooth muscle cells at early gestation by activating the PI3K/mTOR pathway and repressing myostatin expression. 7,8,11,12 Estrogen also supports the expansion of myometrial progenitor-like cells 13 and works together with progesterone to promote the proliferation of leiomyoma side-population cells through regulation of the paracrine WNT signaling from the mature myometrial cells. 14 Moreover, progesterone signaling downregulates the expression of genes that are associated with cell proliferation in cultured human myometrial cells and has a negative effect on vascular smooth muscle proliferation.…”

Estrogen Receptors and Estrogen-Induced Uterine Vasodilation in Pregnancy

“…ER46 has been identified in the vascular endothelial cells (EC) as a mediator of endothelial NO synthase (eNOS) activation in order to encourage the production of NO by estrogens [ 52 ]. Apart from ERα36 and ERα46, ERΔ7 is another recently reported 51-kD variant of ERα66 with the exclusion of exon 7; it acts as a dominant negative repressor of the uterotonic action in myometrium [ 53 ]. The physiological concentrations (100–700 pmol/L) of serum estrogens during the menstrual cycle can only bind to ERα46 and ERα66, but not to ERα36 [ 54 ], which can only bind with E 2 β at a relatively high kD of 2.2 nM compared to the physiological levels of serum estrogens [ 55 ].…”