and C.R.M. Furthermore, the ability of ZEB1 and ZEB2 to repress expression of members of the miR-200 family, as reported elsewhere (17, 18), has not been explored in the myometrium. doi: 10.1152/ajprenal.00638.2016. Throughout most of pregnancy, uterine quiescence is maintained by increased progesterone receptor (PR) transcriptional activity, whereas spontaneous labor is initiated/facilitated by a concerted series of biochemical events that activate inflammatory pathways and have a negative impact on PR function. Primary cultures of mouse myometrial cells were prepared as previously described (33). Data are the mean ± SD values of three replicate experiments (Student’s t test, *P < 0.05, **P < 0.01). Taggart MJ, Europe-Finner GN, Mitchell BF. ZEB1 protein also was significantly decreased in the murine uterus during late gestation, declining to barely detectable in tissues from laboring mice (Fig. Amanda Rodewald, Ivan Rudik, and Catherine Kling talk about the hazards of ozone pollution to birds. With five and six confirmed binding sites in their 3′-UTRs, respectively, ZEB1 and ZEB2 mRNAs (significantly down-regulated in the microarray) were predicted to be the strongest targets of the miR-200 family (10, 12–14) (Fig. Cyclic AMP signalling pathways in the regulation of uterine relaxation. 4B) or CXN-43 and OXTR mRNA (Fig. In this study, we tested the central hypothesis that progesterone maintains uterine quiescence through regulation of active uterine caspase 3. Enter multiple addresses on separate lines or separate them with commas. Moreover, binding was significantly down-regulated in laboring mice (Fig. (A) Diagram depicting P4 injection of mice in late gestation. This suggests that PR predominantly enhances ZEB1 expression by direct binding to the ZEB1 promoter, although other mechanisms may be involved as well. Expression of each miRNA/mRNA was determined by qRT-PCR, normalized to GAPDH/U6, and expressed as the fold increase over 15.5 dpc. Although the absence of a significant inhibitory effect of P4 on miR-200/429 expression was somewhat surprising, we reasoned that this may be attributable to the relatively high endogenous P4 during late gestation in the mouse and to the postulated decline in PR function (1). At present, the exact factors initiating human parturition remain unknown, and labour may occur due to a loss of uterine quiescence, an increase in uterine contractility, or a combination of both. For RU486-induced preterm labor, 15.5-dpc timed-pregnant ICR/CD1 female mice were injected s.c. in the right flank with RU486 [200 μg of RU486 in 1 mL of sterile 5% (vol/vol) ethyl alcohol (EtOH); Sigma] or 5% EtOH (1 mL). Mature miR-200b and miR-429 are significantly up-regulated (A) and ZEB1 and ZEB2 mRNA are significantly down-regulated (B) across late gestation in the mouse myometrium, beginning at 17.5 dpc. Recently, it has been shown that micro-RNAs (miRNAs) play especially powerful roles in vascular smooth muscle cells and in female reproduction, wherein they have been implicated in proliferation, differentiation, and hormone responsiveness (7–9). ... the placental hormone equine chorionic gonadotropin released by endometrial cup acts like LH and FSH and stimulates additional ovulations, … P4 affects the miR-200-ZEB contractile axis via direct induction of ZEB1 expression. Stanfield Z, Amini P, Wang J, Yi L, Tan H, Chance MR, Koyutürk M, Mesiano S. Mol Hum Reprod. hTERT-HM cells were transduced with adenoviral vectors overexpressing ZEB1, ZEB2, or β-gal (control) and embedded into collagen matrices. Cells were infected with recombinant adenoviruses expressing ZEB1, ZEB2, or β-gal, (control) and cultured for 48 h. These, as well as uninfected cells, were embedded into collagen gel matrices and treated with or without oxytocin (10 nM). These culminate in an inflammatory response within the uterus and cervix, which leads to a reduction in PR function (2, 3), exacerbated inflammatory signaling, cervical ripening, and activation of contraction-associated genes within the myometrium. miR-200 family and targets, ZEB1 and ZEB2, modulate uterine quiescence and contractility during pregnancy and labor.  |  A role for CXN-43 and OXTR in myometrial contractility has long been appreciated, because expression of both of these genes enhances receptivity of the uterus to the contractile signals of labor. Diagram of RU486 treatment (A) or LPS treatment (B) to induce preterm labor. Mitidieri E, Vanacore D, Turnaturi C, Sorrentino R, d'Emmanuele di Villa Bianca R. Antioxidants (Basel). 3G); this presumably occurs via ZEB1 suppression of the miR-200 family. 2018 Dec 1;159(12):4033-4042. doi: 10.1210/en.2018-00497. For one-way ANOVA, miR-200b: F(4,20) = 14.82, P < 0.0001; miR-429: F(4,20) = 17.49, P < 0.0001; ZEB1: F(4,20) = 12.71, P < 0.0001; ZEB2: F(4,20) = 5.37, P = 0.004; CXN-43: F(4,20) = 12.93, P < 0.0001; OXTR: F(4,20) = 11.03, P < 0.0001. To investigate whether expression of the miR-200 family and ZEB1 and ZEB2 during pregnancy and labor is conserved from the mouse to the human, we conducted qRT-PCR analysis of RNA from myometrial biopsies of women at term, either not in labor or in labor. The authors declare no conflict of interest. Progesterone maintains uterine quiescence in part by mechanisms that lower expression of various key proteins needed for contractility. We postulated that P4 induction of ZEB1 causes suppression of the miR-200 family, which, in turn, relieves suppression of ZEB2, resulting in its subsequent induction. Interestingly, similar findings have been observed in stable MDCK cell lines overexpressing ZEB1 (17). Together, these findings implicate the miR-200 family and their targets, ZEB1 and ZEB2, as unique P4/PR-mediated regulators of uterine quiescence and contractility during pregnancy and labor and shed light on the molecular mechanisms involved in preterm birth. Expression of each miRNA/mRNA was determined by qRT-PCR, normalized to U6/GAPDH, and expressed as the fold change over vehicle-treated controls. Overexpression of ZEB1 or ZEB2 in primary myometrial cells resulted in a significant reduction in endogenous miR-200b/429 expression at 96 h posttransduction (Fig. Together, these data suggest that ZEB1 is a direct PR target gene. Because of the pronounced inhibitory effect of ZEB1 and ZEB2 on expression of CXN-43 and OXTR, we examined the effects of ZEB1 and ZEB2 overexpression on contractility of uterine myocytes. Therefore, we hypothesize that normal transient stress insults may precondition the uterus and prevent contractility by increasing the capacity of the myometrium to experience ER stress in the absence of precocious increases in adaptive UPR … To identify genes regulated by miRNAs during pregnancy and labor, we performed a gene expression microarray (SI Dataset 2) and compared sets of down-regulated uterine genes at 18.5 dpc with the strongest miR-200b/c/429 TargetScan (Whitehead Institute for Biomedical Research) context scores (11) (Fig. Notably, ZEB1 has two putative progesterone response elements (PREs) in its promoter, although none are apparent in the ZEB2 promoter. The identification of miRNAs as hormonally regulated modulators of gene expression prompted us to investigate their roles in P4 and PR regulation of contraction-associated genes during pregnancy and labor. Data are the mean ± SD values from three replicate experiments (Student’s t test, *P < 0.05, **P < 0.01). We thank Dr. Y. Higashi (Osaka University, Osaka, Japan) for murine ZEB1 and ZEB2 expression plasmids, as well as Dr. A. Pertsemlidis for array analysis, Dr. W. Renthal and Dr. P. Kumar for expertise with ChIP, A. Click for help with immunohistochemistry, and Dr. F. Grinnell and Dr. C. Ho for instruction in collagen matrix assays (University of Texas Southwestern Medical Center). Collectively, our findings suggest that ZEB1 is a key PR target gene in the myometrium that inhibits expression of contraction-associated genes and the miR-200 family throughout most of pregnancy (Fig. Conversely, parturition is associated with a decline in maternal circulating P4 and/or a decrease in the function of the PR, termed “functional P4 withdrawal,” (2, 3) and an increased inflammatory response within the uterus and cervix (4). We do not capture any email address. LPS (1.5 μg in 50 μL of PBS; Sigma) or sterile PBS (50 μL) was carefully infused into each amniotic sac, the uterus was reinserted into the abdominal cavity, and the mouse was allowed to recover. At the end of pregnancy, increased stretch along with greater estrogen dominance raises CAP levels. … Structures and Small Molecule Modulators of Mammalian Adenylyl Cyclases. We have verified the presence of mRNA encoding adenylyl cyclase (AC) isoforms I, II, III, V, VI, VII, VIII and IX in both non-pregnant and pregnant human myometrium, and in isolated myometrial cells maintained in cell culture. These findings illustrate the diversity of potential cAMP generating pathways in human myometrium, and the complexity of the signal transduction systems underlying uterine quiescence. 2000 Jan;164(1):21-30. doi: 10.1677/joe.0.1640021. Epub 2016 Aug 8. In addition, mice with a smooth muscle-specific deletion of the CXN-43 gene manifest a significant delay in the timing of parturition (28). β-actin was used as a loading control. Estrogen receptor alpha isoform ERdelta7 in myometrium modulates uterine quiescence during pregnancy. Oxytocin, a key hormone that enhances uterine contractility at term (24), significantly induced contraction of collagen gel matrices embedded with untransduced and β-gal–transduced hTERT-HM cells (Fig. S3, 24 h following P4 injection, miR-200b/429 were significantly down-regulated in the myometrium as compared with oil-injected controls. During pregnancy uterine quiescence is maintained by elevated levels of circulating progesterone acting through its receptor (PR), whereas decreasing progesterone concentration or activity promotes parturition or abortion [39, 40]. Myometrial contraction is regulated by a number of factors, such as female sexual hormones, the adrenergic receptor (AR) system, ion channels and transmitters. Data are representative of three similar experiments. Paradoxically, during uterine quiescence CRH may act as a myometrial relaxant rather than as a promoter of parturition. Data deposition: The data reported in this paper have been deposited in the Gene Expression Omnibus (GEO) database, www.ncbi.nlm.nih.gov/geo (accession no. There is near-complete homology of the miR-200 family between the mouse and human; the genes cluster identically and differ in their mature sequences by only two nucleotides in the 3′-region of miR-429 (Fig. The temporal up-regulation of the miR-200 family and down-regulation of ZEB1 and ZEB2 expression in the pregnant mouse uterus at 17.5 dpc, which just precedes the time of induction of the contraction-associated genes CXN-43 and OXTR, marks a critical time for transition to a contractile myometrium. 4 D–F). Although premature labor is the leading cause of neonatal morbidity and mortality in developed countries, the signaling mechanisms that maintain uterine quiescence during pregnancy and promote increased uterine contractility leading to labor at term and preterm remain incompletely defined (1). A high content of sialic acid prolongs its half-life compared to its analogue, luteinizing hormone (LH). Get the latest public health information from CDC: https://www.coronavirus.gov, Get the latest research information from NIH: https://www.nih.gov/coronavirus, Find NCBI SARS-CoV-2 literature, sequence, and clinical content: https://www.ncbi.nlm.nih.gov/sars-cov-2/. It may reflect a breakdown in the mechanisms responsible for maintaining uterine quiescence . mmu, Mus musculus. One conserved function of steroid hormone receptors is that they autoregulate the expression of their own genes [16]. 1C). Despite our growing insight into the signals and pathways leading to the initiation of labor, much remains to be discovered regarding the mechanisms whereby the myometrium is transformed from a refractory near-quiescent state to a highly contractile unit capable of responding to a variety of signals from the fetus and mother. Relative gene expression was calculated using the comparative cycle threshold (ΔΔCt) method. This removes the brakes from contractile gene expression, resulting in increased uterine contractility and labor. LPS- and RU486-treated mice were killed on the birth of one pup, and time-matched vehicle-injected mice were killed directly afterward. Prashanth Anamthathmakula. 4D), OXTR (Fig. Uterine activation (Phase 1) This is a priming phase during which the uterus demonstrates increased The resulting elevated miRNAs can then feed back and repress both ZEB1 and ZEB2 (Fig. Adequate uterine contractility is involved in the transport of the semen and gametes and in successful embryo implantation, whereas inadequate uterine contractility may lead to ectopic pregnancies, miscarriages, retrograde bleeding and endometriosis (Leyendecker et al., 2004; Bulletti and de Ziegler, 2005; Kissler et al., 2005). None of the vehicle-injected mice delivered preterm. Therefore, it was of interest to examine the effects of ZEB1 and ZEB2 overexpression on contraction-associated genes in the uterine myometrium. GSE25017). Mean ± SEM values are shown (Student’s t test, *P < 0.05; n = 7 mice per group). We also observed up-regulation of the miR-200 family and down-regulation of ZEB1 and ZEB2 in two different mouse models of preterm labor. Transfection of hTERT-HM cells with miR-200b/429 mimics resulted in a significant reduction in endogenous ZEB1 and ZEB2 expression within 24 h (Fig. Post hysteroscopic progesterone hormone therapy was reported to have encouraging clinical effects in the treatment of endometrial polyps as it is shown to have effectively prevented the recurrence of endometrial polyps, ... 34 and (3) endometrial quiescence, established by steady levels of oestrogen and progesterone. 4H). J Physiol. Our findings, which elucidate a unique regulatory pathway involving the miR-200 family and their targets, ZEB1 and ZEB2, provide insight into the mechanisms by which P4 and PR maintain uterine quiescence throughout most of pregnancy and that mediate the myometrial transformation leading to parturition. Online ISSN 1091-6490. Adenylyl cyclase isoforms in pregnant and non-pregnant human myometrium. None of the vehicle-injected mice went into labor. Endocrinology. Lower uterine segment myometrial tissues were biopsied at term from pregnant women undergoing cesarean section as detailed in SI Materials and Methods. Whilst many studies have aimed to understand the mechanisms underlying uterine contractility there is a relative paucity of data regarding myometrial relaxation. 4H). National Center for Biotechnology Information, Unable to load your collection due to an error, Unable to load your delegates due to an error. HEK293 cells were transfected with various PR expression plasmids and ZEB1-Luciferase reporter constructs using Fugene 6 transfection reagent (Roche) according to the manufacturer’s protocol. hTERT-HM cells were cultured and transduced with recombinant adenoviruses or transfected with miRNA mimics (Qiagen). FSH Actions and Pregnancy: Looking Beyond Ovarian FSH Receptors. (Multiple comparison test compared with 15.5 dpc: *P < 0.05, **P < 0.01; n = 10 mice each for 15.5 dpc and laboring groups, 5 mice each for 16.5–18.5 dpc.) RLX is one of the key hormones in vascularization and differentiation of the endometrium preparing the inner uterine layer for implantation. (H) CXN-43 and OXTR in the same samples as in E and F were significantly up-regulated in laboring myometrium. 2007 Jun 1;7 Suppl 1(Suppl 1):S10. Consequently, after 17.5 dpc, when P4 levels and PR function decline (27), ZEB1 mRNA and protein in the pregnant mouse uterus are significantly reduced. Studies from a number of laboratories, including our own, suggest that P4 and PR maintain uterine quiescence until term by inhibiting expression of contraction-associated genes [e.g., connexin-43 (CXN-43), oxytocin receptor (OXTR), cyclooxygenase 2 (COX-2)] in the myometrium, in part, via anti-inflammatory actions. The decline in PR function near term causes a down-regulation of ZEB1 gene expression, which, in turn, results in derepression and up-regulation of miR-200b/429 expression. DNA was purified and analyzed by qPCR as detailed in SI Materials and Methods. Download in PowerPoint. To compare their temporal expression in the mouse myometrium during late gestation, we next examined miR-200b/429 and ZEB1 and ZEB2 by quantitative RT-PCR (qRT-PCR) from 15.5 dpc to labor. The cells were cultured with or without P4 (10−7 M) for 24 h, and luciferase activity was assayed, normalized to β-gal, and expressed as the fold increase over vector-transfected control cells. 1F). (G) Overexpression of ZEB1 causes induction of ZEB2 mRNA expression. To assess the effects of P4 injection on miR-200b/miR-429 expression in the myometrium in the absence of endogenous P4, we conducted experiments using ovariectomized mice injected with P4 (1 mg). Through overexpression experiments, we show that miR-200s repress endogenous ZEB1 and ZEB2 expression in human myometrial cells. 2017 Apr;69(2):93-139. doi: 10.1124/pr.116.013078. (C) ZEB1 protein in nuclear extracts of murine myometrium mirrors the decline in ZEB1 mRNA. High-frequency uterine contractions (UC) at the time of embryo transfer have been shown to hamper the outcome of in-vitro fertilization (IVF). Estrogen receptor alpha isoform ERdelta7 in myometrium modulates uterine quiescence during pregnancy 4G). Several attempts to quantify ZEB2 protein with commercially available antibodies were unsuccessful. Epub 2017 May 24. Because of these collective findings, we suggest that the observed decline in ZEB2 during late gestation and in response to RU486 treatment is attributable to the rise in miR-200 family expression, which, in turn, represses both ZEB1 and ZEB2 (Fig. The present research sheds light on this extremely important transitional period within the maternal uterus. 2016 Nov 1;594(21):6369-6393. doi: 10.1113/JP272320. Adiponectin is the most abundant hormone released by adipocytes , with wide‐ranging effects on energy homeostasis , inflammation , and ... Our findings add adiponectin to a roster of endogenous uterine quiescence factors (e.g., progesterone, relaxin) that maintain pregnancy by counteracting procontractile factors such as distension, infection, hemorrhage, and rupture of … 4B). The levels of each mRNA/miRNA were normalized to h36B4/U6 and expressed as the fold change over control. However, the role of oxytocin and OXTR in normal parturition is uncertain, because oxytocin gene KO mice undergo parturition and give birth to live young (29) and mice deficient in OXTR manifest normal timing and duration of parturition (30). CI. analyzed data; and N.E.R. In addition, it promotes expansion of the birth canal by loosening the pubic symphysis during pregnancy and relaxation of the cervix at birth. Gene expression microarray assays were performed (University of Texas Southwestern Medical Center) on the same 36 samples, as detailed further in SI Materials and Methods. In the present study, we show that members of the miR-200 family in both the mouse and human uterus are significantly induced during late gestation, repress the zinc finger E-box binding homeobox proteins ZEB1 and ZEB2, and mediate myometrial contractility. 4H). Differential impact of acute and prolonged cAMP agonist exposure on protein kinase A activation and human myometrium contractile activity. TREK-1 channel, a stretch-activated tetraethyl ammonium-insensitive potassium (K+) channel, has been described in smooth muscle of human myometrium. Mean ± SEM values are shown (Student’s t test, *P < 0.05; n = 14 for laboring myometrium, n = 23 for nonlaboring controls). 3F). (G) Overexpression of ZEB1 and ZEB2 in hTERT-HM cells inhibits oxytocin-mediated contraction. We also wanted to determine whether similar changes in miR-200b/429 and ZEB1 and ZEB2 expression were associated with preterm labor. Protein expression of ZEB1 also was suppressed at term in human myometrial samples (Fig. Cells starved of endogenous steroids (see MATERIALS AND METHODS) were grown to 100% confluence (t 0h)and treated with 10 … Figure 8. Expression of PR in responsive tissues is driven by estrogen-bound ER and, … Recent findings suggest that progesterone action to maintain uterine quiescence may be indirect by inhibiting expression of contractile genes within the uterus and cervix and blocking the production of chemokines that promote chemotaxis of immune cells [ 11 ]. Using the mouse as our model system, we examined, … Experimental strategy for hormone additions to human uterine smooth muscle cells (hUtSMCs). Furthermore, by means of immunoblotting and immunocytochemistry, we have demonstrated the expression of these isoforms as membrane-associated AC proteins, and identified changes in individual AC isoform expression during gestation. Densitometry analysis of blots comparing P4-treated mice with vehicle controls revealed that P4 causes a significant increase in ZEB1 protein (Student’s t test, P < 0.05; n = 7 mice per group). 1E) and ZEB1 and ZEB2 down-regulated in laboring human myometrium as compared with the myometrium of nonlaboring women at term (Fig. As can be seen, P4 had a pronounced effect on the up-regulation of ZEB1 promoter activity in cells cotransfected with WT PR-B; however, this was largely prevented in cells cotransfected with mutPR-BDBD (Fig. Experimental objectives: Activation of the oxytocin receptor (OTR) induces phospholipase C induced PIP 2 turnover in the human uterus. was supported by the National Institutes of Health (Grant 5-P01-HD11149) and the March of Dimes Birth Defects Foundation (Grant 21-FY07-601). miR-200b/429 are up-regulated and ZEB1 and ZEB2 are down-regulated in two models of preterm labor. Abstract Throughout most of pregnancy, uterine quiescence is maintained by increased progesterone receptor (PR) transcriptional activity, whereas spontaneous labor is initiated/facilitated by a concerted series of biochemical events that activate inflammatory pathways and have a negative impact on PR function. It is accepted that whilst hormones such as oxytocin, vasopressin and prostaglandin F2alpha induce myometrial contractions, essentially via an elevation of intracellular calcium, other ligands, such as beta-adrenoceptor agonists, calcitonin gene-related peptide, and prostaglandin E2, promote uterine quiescence via their ability to increase intracellular cyclic AMP levels. J Clin Invest. To test this hypothesis, primary cultures of mouse myometrial cells were infected with recombinant adenoviruses expressing ZEB1 or β-gal (control) and ZEB2 mRNA was analyzed as a function of time. 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