The microRNA (miR)-199a/214 Cluster Mediates Opposing Effects of Progesterone and Estrogen on Uterine Contractility during Pregnancy and Labor

Abstract

Progesterone (P(4)) and estradiol-17β (E(2)) play critical and opposing roles in regulating myometrial quiescence and contractility during pregnancy and labor. Although these contrasting hormonal effects are likely mediated via differential regulation of inflammatory and contractile genes, the underlying mechanisms remain incompletely understood. Recently we discovered that targets of the microRNA (miR)-200 family, transcription factors zinc finger E-box binding homeobox (ZEB)-1 and ZEB2, serve as P(4)/progesterone receptor-mediated regulators of uterine quiescence during pregnancy. In the present study, we found that levels of the clustered miRNAs, miR-199a-3p and miR-214, were significantly decreased in laboring myometrium of pregnant mice and humans and in an inflammatory mouse model of preterm labor, whereas the miR-199a-3p/miR-214 target, cyclooxygenase-2, a critical enzyme in synthesis of proinflammatory prostaglandins, was coordinately increased. Overexpression of miR-199a-3p and miR-214 in cultured human myometrial cells inhibited cyclooxygenase-2 protein and blocked TNF-α-induced myometrial cell contractility, suggesting their physiological relevance. Notably, E(2) treatment of ovariectomized mice suppressed, whereas P(4) enhanced uterine miR-199a-3p/214 expression. Intriguingly, these opposing hormonal effects were mediated by ZEB1, which is induced by P(4), inhibited by E(2) and activates miR199a/214 transcription. Together, these findings identify miR-199a-3p/miR-214 as important regulators of myometrial contractility and provide new insight into strategies to prevent preterm birth.

Advances in the role of oxytocin receptors in human parturition

“…More recently, miRNAs have been implicated in hormone responsiveness and the regulation of key gene expression pathways involved in parturition [58]. Enquobahrie et al reported a distinct group of miRNAs, such as hsa-miR-199a-3p, -202-5p, and -214-3p, differentially expressed in human fetal membranes in term labouring samples [59].…”

MicroRNAs, immune cells and pregnancy

“…We are only beginning to discover the roles of miRNAs in reproduction. miRNAs have been implicated in endometrial receptivity, [34][35][36] implantation, 37-42 labor [43][44][45][46][47] and even spontaneous fetal loss in the pig. 48,49 In the uterus, most of the physiological changes occurring over the estrous/menstrual cycle and during pregnancy are driven by the ovarian hormones.…”

Molecular Regulation of Parturition: A Myometrial Perspective

“…As noted, the expression of COX-2 increases in the pregnant myometrium during late gestation and is believed to be critical for the increase in contractile PGF 2 a required for the progression to labor. Our studies revealed that COX-2 also is a bona fide target of miR-214 (Williams et al 2012b). In pregnant mouse myometrium, Cox-2 protein levels were significantly increased at 18.5 dpc and during labor, compared with 15.5 dpc, as miR-199a-3p and miR-214 reciprocally declined.…”

“…Estrogens induce an influx of macrophages and neutrophils into the uterus and antagonize the anti-inflammatory actions of P 4 / PR (Tibbetts et al 1999;Mesiano et al 2002). ERa activation also promotes labor by enhancing transcription of genes for OXTR (Murata et al 2003), CX43 (Piersanti and Lye 1995) and COX-2 (Mesiano et al 2002;Williams et al 2012b), which is expressed at low to undetectable levels in the uterus throughout most of pregnancy, but is highly up-regulated at term (Tsuboi et al 2000;Engstrom 2001;Williams et al 2012b). MicroRNAs that were significantly down-regulated near term in our microarray analysis included miR-199a-3p, known to target COX-2 mRNA (Chakrabarty et al 2007) and miR-214, which targets PTEN and activates the Akt pathway Yin et al 2010).…”