Molecular Regulation of Parturition: A Myometrial Perspective

Abstract

The molecular mechanisms that maintain quiescence of the myometrium throughout most of pregnancy and promote its transformation to a highly coordinated contractile unit culminating in labor are complex and intertwined. During pregnancy, progesterone (P4) produced by the placenta and/or ovary serves a dominant role in maintaining myometrial quiescence by blocking proinflammatory response pathways and expression of so-called "contractile" genes. In the majority of placental mammals, increased uterine contractility near term is heralded by an increase in circulating estradiol-17β (E2) and/or increased estrogen receptor α (ERα) activity and a sharp decline in circulating P4 levels. However, in women, circulating levels of P4 and progesterone receptors (PR) in myometrium remain elevated throughout pregnancy and into labor. This has led to the concept that increased uterine contractility leading to term and preterm labor is mediated, in part, by a decline in PR function. The biochemical mechanisms for this decrease in PR function are also multifaceted and interwoven. In this paper, we focus on the molecular mechanisms that mediate myometrial quiescence and contractility and their regulation by the two central hormones of pregnancy, P4 and estradiol-17β. The integrative roles of microRNAs also are considered.

Figure 1.

Molecular mechanisms for P₄/PR regulation of myometrial quiescence. PR maintains myometrial quiescence, in part, by blocking activation of NF-κB and preventing its transcriptional activation of proinflammatory genes, such as COX-2. P₄/PR exerts this action by increasing expression of the NF-κB inhibitor, IκBα, which prevents activation and nuclear translocation of NF-κB p50 and p65 and by induction of MKP-1/DUSP1, which inhibits p38 MAPK activation and NF-κB p65 nuclear translocation. PR also inhibits activation of CAP genes (e.g., COX-2) by direct interaction/tethering to NF-κB bound to response elements in the promoters of these genes. In addition, PR prevents myometrial contractility by increasing expression of ZEB1, which inhibits expression of CX43 and OXTR.

Figure 2.

P₄/PR modulation of the ZEB1-miR-200 negative feedback loop regulates contractile gene expression in the pregnant myometrium. During pregnancy, P₄/PR increase expression of ZEB1, which acts to suppress the miR-200 family, as well as contraction-associated genes. Decreased expression of the miR-200 family relieves suppression of ZEB2 (as well as ZEB1), resulting in further down-regulation of contractile genes. Near term, a decrease in circulating P₄ and/or a decrease in PR function results in down-regulation of ZEB1 expression, and, in turn, an up-regulation of the miR-200 family, further suppressing ZEB1 and ZEB2. This removes the brakes from contractile gene expression, resulting in increased uterine contractility and labor.

Figure 3.

Increased miR-200 expression near term inhibits PR function by targeting STAT5b and enhancing P₄ metabolism in myometrium. During pregnancy, elevated P₄/PR function increases expression of transcription factor ZEB1, which inhibits expression of miR-200a and other members of the miR-200 family. The decreased levels of miR-200 enhance expression of STAT5b, which represses 20α-HSD to sustain elevated P₄ levels within the myometrium. During the transition to term and preterm labor, an increased inflammatory response promotes a decline in PR function in myometrium, resulting in decreased levels of ZEB1, which releases repression of the miR-200 family. The increased levels of miR-200s inhibit STAT5b expression, releasing repression of 20α-HSD. The increase in 20α-HSD expression, in turn, catalyzes metabolism of P₄ to reduce local P₄ levels in the myometrium and further promote the progression of labor. The decline in PR function may act in a positive feed forward manner to further increase miR-200 expression, suppress STAT5b, and up-regulate 20α-HSD.

Figure 4.

ZEB1 serves a pivotal role by mediating opposing actions of P₄ and E₂ on myometrial contractility during pregnancy and labor. During pregnancy, increased levels of P₄ and increased PR function promote up-regulation of ZEB1 in myometrium. ZEB inhibits expression of the miR-200 family and suppresses OXTR and CX43. The decline in miR-200 levels further up-regulates ZEB1 and increases ZEB2, which bind response elements upstream of the miR-199a/214 cluster to enhance its expression, causing suppression of COX-2, and preventing synthesis of contractile prostaglandins. The decreased levels of miR-200s allow up-regulation of another target, STAT5b, which inhibits expression of 20α-HSD, allowing local levels of P₄ in myometrium to remain elevated. During the transition to labor, the decline in myometrial P₄/PR function and increase in circulating E₂ and ERα activity cause down-regulation of ZEB1. This leads to induction of the miR-200 family, which further suppresses ZEB1 and ZEB2, allowing up-regulation of OXTR and CX43 expression. The decline in ZEBs also causes decreased expression of the miR199a/214 cluster, which allows up-regulation of COX-2 and increased synthesis of contractile prostaglandins. The increase in miR-200 expression inhibits STAT5b, permitting increased transcription of 20α-HSD to promote increased metabolism of P₄ to inactive products in myometrium. Collectively, these molecular events contribute to the initiation of uterine contractility, leading to labor.