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MicroRNAs—mediators of myometrial contractility during pregnancy and labour

Nature Reviews Endocrinology volume 9, pages 391–401 (2013)Cite this article

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Abstract

The maintenance of myometrial quiescence and initiation of contractility, which lead to parturition at term and preterm, involve a shifting equilibrium between anti-inflammatory and proinflammatory signalling pathways. Progesterone (P4), acting through the progesterone receptor (PR), has an essential and multifaceted role in the maintenance of myometrial quiescence. This effect of P4–PR signalling is mediated, in part, by its anti-inflammatory actions and capacity to repress the expression of genes that encode proinflammatory cytokines, such as IL-1 and IL-6, and contraction-associated proteins, such as OXTR, GJA1 and PTGS2. By contrast, increased expression of genes that ultimately lead to parturition is mediated by enhanced inflammatory and estradiol-17β (E2) and estrogen receptor α signalling, which reduce PR function, thus further intensifying the inflammatory response. To obtain a more complete understanding of the molecular events that underlie the transition of the pregnant myometrium from a refractory to a contractile state, the roles of microRNAs, their targets, and their transcriptional and hormonal regulation have been investigated. This article reviews the actions of the miR-200 family and their P4-regulated targets—the transcription factors ZEB1, ZEB2 and STAT5B—in the pregnant myometrium, as well as the role of miR-199a-3p and miR-214 and their mutual target PTGS2. The central role of ZEB1 as the mediator of the opposing actions of P4 and E2 on myometrial contractility will be highlighted.

Key Points

  • Progesterone (P4), acting via the progesterone receptor (PR), maintains uterine quiescence in part by increasing the expression of ZEB1 and ZEB2, which inhibit the contraction-associated genes OXTR and GJA1

  • The initiation of myometrial contractility is mediated by an increased inflammatory response, an associated increase in 17β-estradiol (E2) and estrogen receptor (ERα) signalling and a decline in PR function

  • Near term, the myometrial inflammatory response is promoted by physical and hormonal signals from mother and fetus; in preterm labour, the increased inflammatory response is commonly induced by a bacterial infection

  • Expression of the miR-200 family increases in mouse and human myometrium near term and suppresses ZEB1 and ZEB2 levels, which results in the de-repression of contractile genes and increased myometrial contractility

  • Increased miR-200 expression near term also inhibits STAT5B; decreased STAT5B levels de-repress 20α-hydroxysteroid dehydrogenase and increase myometrial metabolism of P4

  • Increased E2–ERα signalling and the decline in PR function near term mediate decreased expression of ZEB1, and of miR-199a-3p and miR-214, which contributes to the induction of PTGS2

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Figure 1: P4–PR regulation of myometrial quiescence.
Figure 2: The increased inflammatory response associated with parturition.
Figure 3: Chromosomal location and seed sequences of members of the miR-200 family and the miR-199a/214 cluster.
Figure 4: Schematic representation of the pivotal role of ZEB1 and ZEB2 during pregnancy and labour.

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Acknowledgements

The authors' research was supported by the National Institutes of Health (NIH 5-P01-HD011149) and the March of Dimes Foundation (Prematurity Research Grant No. 21-FY11-30).

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Authors and Affiliations

  1. Department of Pediatrics, Children's Medical Center Dallas, 1935 Medical District Drive, Dallas, 75235, TX, USA

    Nora E. Renthal

  2. Departments of Biochemistry and Obstetrics and Gynecology, the University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, 75390, TX, USA

    Koriand'r C. Williams & Carole R. Mendelson

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Renthal, N., Williams, K. & Mendelson, C. MicroRNAs—mediators of myometrial contractility during pregnancy and labour. Nat Rev Endocrinol 9, 391–401 (2013). https://doi.org/10.1038/nrendo.2013.96

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