uterine quiescence hormone

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. doi: 10.1186/1471-2393-7-S1-S10. Am J Physiol Renal Physiol. These findings illustrate the diversity of potential cAMP generating pathways in human myometrium, and the complexity of the signal transduction systems underlying uterine quiescence. NLM This question is for testing whether or not you are a human visitor and to prevent automated spam submissions. Antibodies directed against ZEB1 (generously provided by Douglas Darling, University of Louisville, Louisville, KY) (32) were used to determine protein levels by immunoblotting. S1 C and D). 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. Epub 2017 May 24. In an effort to identify miRNAs that mediate myometrial transition to a contractile phenotype in preparation for labor, we performed microarray analysis to compare the miRNA expression profile in RNA from isolated myometrium of three pools (six uteri each) from eighteen 15.5 d post-coitum (dpc) vs. three pools (six uteri each) from eighteen 18.5 dpc (with term labor being 19.0 dpc) pregnant mice. Epub 2008 Nov 20. 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. Expression of each miRNA/mRNA was determined by qRT-PCR, normalized to U6/GAPDH, and expressed as the fold change over vehicle-treated controls. 3C) and protein (Fig. As mentioned, ZEBs act as transcriptional repressors by recruiting corepressors to the promoters of target genes (20). Mean ± SEM values are shown (Student’s t test, *P < 0.05, **P < 0.01; n = 7 per group). Enter multiple addresses on separate lines or separate them with commas. USA.gov. Interestingly, similar findings have been observed in stable MDCK cell lines overexpressing ZEB1 (17). Cell-embedded matrices were treated with 10 nM oxytocin and assayed for contractility as described in SI Materials and Methods. These collective findings suggest that P4 can inhibit miR-200b/429 expression and that this may be mediated, in part, via P4 induction of ZEB1. P4 maintains uterine quiescence during pregnancy, while estrogen induces uterine contraction at labor (49–51). 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. CXN-43 and OXTR mRNA showed temporal expression profiles that were coordinately up-regulated with down-regulation of ZEB1 and ZEB2 in the pregnant mouse uterus during late gestation (Fig. This negative feedback loop may explain the kinetics of miR-200b/429, ZEB1, and ZEB2 expression throughout gestation and in preterm labor. Moreover, binding was significantly down-regulated in laboring mice (Fig. 2017 Aug 1;313(2):F535-F546. Decreased expression of the miR-200 family relieves suppression of ZEB2 (as well as ZEB1), resulting in further down-regulation of contractile genes. Expression of each miRNA/mRNA was determined by qRT-PCR, normalized to U6/GAPDH, and depicted as the fold increase over vehicle-treated controls. 3C). Consistent with the inverse regulation of miR-200b/429, ZEB1, and ZEB2 observed during late gestation in the mouse and human (Fig. (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.) CRISPR-Cas9 gene editing can improve the effectiveness of spermatogonial stem cell transplantation in mice and livestock, a study finds. Furthermore, few studies have … Our findings in pregnant mice and cultured cells (Fig. None of the P4-treated animals progressed to labor at 19.0 dpc. Cyclic AMP signalling pathways in the regulation of uterine relaxation. contributed new reagents/analytic tools; N.E.R. 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. RU486 induced labor within 12 h in 7 of 7 injected mice; LPS induced preterm labor within 12–18 h in 7 of 10 injected mice. Diagram of RU486 treatment (A) or LPS treatment (B) to induce preterm labor. S3, 24 h following P4 injection, miR-200b/429 were significantly down-regulated in the myometrium as compared with oil-injected controls. Near term, a decrease in circulating P4 and/or a decrease in PR function results in down-regulation of ZEB1 expression, and, in turn, up-regulation of the miR-200 family, further suppressing ZEB1 and ZEB2. 2. 4F) at 15.5 dpc. Based on investigations from our laboratory and others, we postulate that the timing of parturition is mediated by integrated signaling pathways from both the mother and maturing fetus (25). The temporal regulation of miR-200b/429, ZEB1, and ZEB2 beginning at 17.5 dpc is of particular interest because this marks an important time of transition in the maternal uterus, during which there is a switch from quiescence and resistance to inflammatory signals to increased receptivity to stimuli that trigger uterine contractility (26). 1E) and ZEB1 and ZEB2 down-regulated in laboring human myometrium as compared with the myometrium of nonlaboring women at term (Fig. RNA was DNase-treated (Invitrogen) and reverse-transcribed using the SuperScript III-RT kit (Invitrogen) or TaqMan miRNA reverse transcription kit (Applied Biosystems). 2017 Apr;69(2):93-139. doi: 10.1124/pr.116.013078. Given the temporal relationship of the decline in ZEB1 and ZEB2 to the induction of labor, we examined whether these transcriptional repressors regulate contraction-associated genes in the uterine myometrium. National Center for Biotechnology Information, Unable to load your collection due to an error, Unable to load your delegates due to an error. Steroid hormone regulation of myometrial cell to cell communication ; progeterone causes … Clipboard, Search History, and several other advanced features are temporarily unavailable. Would you like email updates of new search results? Study design: A multicenter, double-blind, placebo-controlled trial was designed for patients in preterm labor who responded to early intravenous treatment with atosiban. Taken together, our findings implicate a previously undiscovered pathway in the regulation of uterine contractility during pregnancy and parturition that is conserved from mice to humans and may ultimately open avenues for development of effective therapeutics for prevention of preterm labor. This site needs JavaScript to work properly. P4 affects the miR-200-ZEB contractile axis via direct induction of ZEB1 expression. Download. mmu, Mus musculus. 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). Although the evidence is still limited, a growing body of research suggests music may have beneficial effects for diseases such as Parkinson’s. wrote the paper. To determine whether the induction of ZEB1 expression by P4 is attributable to the direct binding of PR to the ZEB1 promoter, we cotransfected HEK293 cells with a reporter construct containing 978 bp of the ZEB1 5′-flanking sequence subcloned upstream of the luciferase gene and with an expression vector containing either WT PR-B or PR-B with an inactivating mutation in the DNA-binding domain (mutPR-BDBD). 3D) were significantly increased in the myometrium of the P4-injected mice, whereas ZEB2 mRNA was unaffected (Fig. Expression of each miRNA/mRNA was determined by qRT-PCR, normalized to U6/h36B4, and expressed as the fold increase over nonlaboring controls. Pineda RH, Nedumaran B, Hypolite J, Pan XQ, Wilson S, Meacham RB, Malykhina AP. 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. 2000 Jan;164(1):21-30. doi: 10.1677/joe.0.1640021. 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). Overexpression of miR-200b/429 mimics, ZEB1, and ZEB2 regulates contraction-associated genes and human myometrial cell contractility. We do not capture any email address. 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). The miRNA microarray was performed (LC Sciences) on 18 biological replicates of murine myometrium at 15.5 dpc and on an equal number of replicates at 18.5 dpc. We further demonstrated that ZEB1 is directly up-regulated by the action of progesterone (P4)/PR at the ZEB1 promoter. Following transduction of myometrial cells with recombinant adenoviruses expressing either ZEB1 or ZEB2, CXN-43 and OXTR mRNA levels were found to be significantly suppressed at 48 h (Fig. miR-200b/429 were significantly up-regulated (E) and ZEB1 and ZEB2 mRNA were significantly down-regulated (F) in laboring myometrium as compared with nonlaboring controls. In ChIP studies, we observed that endogenous ZEB1 binds to the promoters of the OXTR, CXN-43, and miR200b-a-429 cluster and that ZEB1 binding significantly declines between 15.5 and 18.5 dpc, in concert with the gestational up-regulation of expression of these genes. Because ZEB1 directly binds and represses the miR-200b/429 promoter (17, 18) (Fig. Densitometry analysis of all three series revealed a significant decrease in ZEB1 protein between 15.5 dpc and labor (Student’s t test, P < 0.05; n = 3 mice per group). Notably, ZEB1 has two putative progesterone response elements (PREs) in its promoter, although none are apparent in the ZEB2 promoter. 1B). 17-295; Millipore) according to the manufacturer’s instructions and ZEB1 antibody (H-102, SC-25388; Santa Cruz), myometrial tissues from timed-pregnant ICR mice (15.5 dpc and in labor) were subjected to ChIP. 1C). 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. 3B). Excitingly, we observed that ZEB1 and ZEB2 inhibit expression of the contraction-associated genes, oxytocin receptor and connexin-43, and block oxytocin-induced contractility in human myometrial cells. 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/. The miR-200 family was found to be up-regulated (Fig. Experimental strategy for hormone additions to human uterine smooth muscle cells (hUtSMCs). Therefore, these relaxatory hormones, together with progesterone, control contractile pathways within the gravid uterus and collectively ensure myometrial quiescence during most of pregnancy. In this study, we uncovered a previously undescribed regulatory pathway whereby micro-RNAs (miRNAs) serve as hormonally modulated and conserved mediators of contraction-associated genes in the pregnant uterus in the mouse and human. 4B) or CXN-43 and OXTR mRNA (Fig. (C) hTERT-HM cells were infected with recombinant adenoviruses expressing ZEB1, ZEB2, or β-gal (control); CXN-43 and OXTR mRNA levels were analyzed by qRT-PCR 48 h posttransduction. Mice found to have vaginal plugs at 0600 hours the following day were considered to be 0.5 dpc. 2019 Jul 1;25(7):408-422. doi: 10.1093/molehr/gaz028. (G) ZEB1 protein expression was decreased in nuclear extracts of laboring myometrium. 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). Thus, it is the balance between uterine stress-mediated activation of non-apoptotic CASP3 and augmented adaptive UPR signaling that facilitates quiescence. Mice were considered in labor on birth of one pup. The appropriate timing of the onset of labor is critical to a successful pregnancy, with potentially devastating consequences resulting to both the mother and child with the onset of preterm labor. 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. 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. Primer sets are listed in SI Materials and Methods. Affiliations. It is accepted that whilst hormones such as oxytocin, vasopressin and prostaglandin F2α induce myometrial contractions, essentially via an elevation of intracellular calcium, other ligands, such as β‐adrenoceptor agonists, calcitonin gene‐related peptide, and prostaglandin E2, promote uterine quiescence via their ability to increase intracellular cyclic AMP levels. The action of oxytocin as an uterotonic agent is widely accepted. Data shown are the mean ± SEM values of two replicate experiments (Student’s t test, *P < 0.05; n = 10 mice per group). Treatment of the cells with P4 (10−7 M) for 12 or 24 h caused a pronounced induction of ZEB1 mRNA, whereas no effect of P4 on ZEB2 expression was evident (Fig. HHS mmu, Mus musculus. and C.R.M. Uterine Quiescence: The Role of Cyclic AMP Uterine Quiescence: The Role of Cyclic AMP Price, Sarah A.; Bernal, Andrés López 2001-03-01 00:00:00 It is accepted that whilst hormones such as oxytocin, vasopressin and prostaglandin F2α induce myometrial contractions, essentially via an elevation of intracellular calcium, other ligands, such as β‐adrenoceptor agonists, calcitonin gene‐related … Progesterone exhibits anti-inflammatory properties that maintain uterine quiescence. The resulting elevated miRNAs can then feed back and repress both ZEB1 and ZEB2 (Fig. Using the mouse as our model system, we examined, … 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. Data are representative of three similar experiments. Estrogen receptor alpha isoform ERdelta7 in myometrium modulates uterine quiescence during pregnancy. By using a multiple array-based approach, we were able to uncover gene networks outside the arsenal of genes known to be important in mammalian parturition. 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. Altered expression and modulation of the two-pore-domain (K. International Union of Basic and Clinical Pharmacology. 4C). IL, laboring myometrium; NIL, nonlaboring control. miR-200b/429 are significantly up-regulated in RU486-induced (C) and LPS-induced (D) preterm labor. (A) Transfection of hTERT-HM cells with miRmimics of miR-200b/429 causes a significant reduction in endogenous ZEB1 and ZEB2 within 24 h. (B) Primary murine myometrial cells were infected with recombinant adenoviruses expressing ZEB1, ZEB2, or β-gal (control); levels of miR-200b and miR-429 were analyzed by qRT-PCR 96 h posttransduction. Epub 2016 Aug 8. In light of recent results, they’re not so sure. β-actin was used as a loading control. (D) Contraction-associated genes CXN-43 and OXTR were significantly up-regulated in the same samples as in A and B, beginning at 18.5 dpc. The removal of progesterone, that is, progesterone withdrawal , directly precedes progression of phase 1 into phase 2 of parturition. This suggests that PR predominantly enhances ZEB1 expression by direct binding to the ZEB1 promoter, although other mechanisms may be involved as well. 1), both models of preterm labor resulted in markedly decreased expression of ZEB1 and ZEB2 mRNA and ZEB1 protein (Fig. IL, laboring myometrium; NIL, nonlaboring control. ZEB1 and ZEB2 mRNA levels in the same tissue samples as in C and D are decreased with RU486-induced (E) or LPS-induced (F) preterm labor. Mitidieri E, Vanacore D, Turnaturi C, Sorrentino R, d'Emmanuele di Villa Bianca R. Antioxidants (Basel). DNA was purified and analyzed by qPCR as detailed in SI Materials and Methods. (A) Diagram depicting P4 injection of mice in late gestation. (H) During pregnancy, P4 and PR increase expression of ZEB1, which acts to suppress the miR-200 family as well as contraction-associated genes. López Bernal A, Rivera J, Europe-Finner GN, Phaneuf S, Asbóth G. BMC Pregnancy Childbirth. Interestingly, P4 and PR do not directly regulate ZEB2 in the mouse myometrium or in cultured human cells. Contraction of the gels was assessed after 24 h by measurement and calculation of mean gel area (mm2). Mean ± SEM values are shown (Student’s t test, *P < 0.05; n = 7 mice per group). 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). For these experiments, vehicle-injected mice were killed in labor (on the birth of one pup) and time-matched P4-treated animals were killed directly afterward. β-actin was used as a loading control. S3). Animals were injected with a single s.c. injection of RU486 (200 μg) or intraamniotic injections of 1.5 μg of LPS into each sac at 15.5 dpc. 2A) or by intraamniotic injections of the bacterial endotoxin LPS (Fig. Experiments were repeated twice with similar results. Progesterone maintains uterine quiescence in part by mechanisms that lower expression of various key proteins needed for contractility. LPS- and RU486-treated mice were killed on the birth of one pup, and time-matched vehicle-injected mice were killed directly afterward. These findings suggest that alterations in myometrial expression of miR-200b/429, ZEB1, and ZEB2 may play a role in the induction of preterm labor. FSH Actions and Pregnancy: Looking Beyond Ovarian FSH Receptors. adrenal gland to produce cortisol -Prostaglandins: lipids hormones respo nsible for uterine contraction (stimulate smooth . 1G). 3G); this presumably occurs via ZEB1 suppression of the miR-200 family. 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. (E) ZEB1 but not ZEB2 mRNA levels are induced in T74D cells treated with 10−7 M P4 for 12 or 24 h. Expression of each gene was determined by qRT-PCR, normalized to h36B4, and expressed as the fold increase over vehicle-treated control cells. Data are the mean ± SD values from three replicate experiments (Student’s t test, *P < 0.05). At the end of pregnancy, increased stretch along with greater estrogen dominance raises CAP levels. However, we observed in primary cultures of mouse myometrial cells that overexpression of ZEB1 caused up-regulation of ZEB2 mRNA (Fig. 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. hTERT-HM cells were transduced with adenoviral vectors overexpressing ZEB1, ZEB2, or β-gal (control) and embedded into collagen matrices. J Clin Invest. The low progesterone concentration could be the possible cause of abortion in dexamethasone treated sheep in this study. To investigate the regulation of ZEB1 and ZEB2 by members of the miR-200 family in the myometrium, we transfected mimics of miR-200b and miR-429 into an immortalized human myometrial cell line (hTERT-HM) (19). Copyright © 2021 National Academy of Sciences. 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. 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. Mean ± SEM values are shown. We have verified the presence of mRNA encoding adenylyl cyclase (AC) isoforms I, II, III, V, VI, VII, VIII Densitometry analysis of blots comparing uterine nuclear extracts from RU486- and LPS-treated mice with vehicle-injected controls revealed a significant reduction in ZEB1 protein with preterm labor (Student’s t test, *P < 0.05; n = 7 mice per group). Talk about the hazards of ozone pollution to birds impact of acute and prolonged cAMP agonist on... Expression by direct binding to the promoters of target genes ( 20 ) have … the of... Purified and analyzed by qPCR as detailed in SI Materials and Methods increase ZEB2 expression between 15.5 dpc term. Identical in hCG, LH, follicle-stimulating hormone, and ZEB2 expression human! Progesterone concentration could be the possible cause of abortion in dexamethasone treated sheep in study... Action of progesterone, cyclic AMP signalling pathways in the universe came from uterine.... 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