uterine quiescence hormone

(D) ZEB1 protein in myometrial nuclear extracts is increased by P4 treatment. 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. 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. It is increased in laboring pregnant myometrium prior to the onset of labor and attracts leukocytes from the circulation to the myometrium. These findings illustrate the diversity of potential cAMP generating pathways in human myometrium, and the complexity of the signal transduction systems underlying uterine quiescence. 4H). Cell-embedded matrices were treated with 10 nM oxytocin and assayed for contractility as described in SI Materials and Methods. As mentioned, ZEBs act as transcriptional repressors by recruiting corepressors to the promoters of target genes (20). These contraction-associated proteins (CAPs) include the oxytocin receptor, prostaglandin F receptor, and connexin-43. At the end of pregnancy, increased stretch along with greater estrogen dominance raises CAP levels. (B) miR-200b/429 are only modestly down-regulated by exogenous P4 treatment during late gestation. 3B). Interplay of transcriptional signaling by progesterone, cyclic AMP, and inflammation in myometrial cells: implications for the control of human parturition. COVID-19 is an emerging, rapidly evolving situation. 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. In addition, it promotes expansion of the birth canal by loosening the pubic symphysis during pregnancy and relaxation of the cervix at birth. Cyclic AMP signalling pathways in the regulation of uterine relaxation. This study was designed to compare the efficacy and safety of atosiban with those of placebo maintenance therapy in women with preterm labor who achieved uterine quiescence with intravenous atosiban. S3, 24 h following P4 injection, miR-200b/429 were significantly down-regulated in the myometrium as compared with oil-injected controls. 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. 3C). 3G); this presumably occurs via ZEB1 suppression of the miR-200 family. Interestingly, P4 and PR do not directly regulate ZEB2 in the mouse myometrium or in cultured human cells. analyzed data; and N.E.R. Although regulation of uterine contraction by steroid hormones during pregnancy and parturition has been studied, few reports have focused on this issue in non-pregnant animals. P4 injection had a modest effect to decrease myometrial expression of miR-200b/429 (Fig. None of the P4-treated animals progressed to labor at 19.0 dpc. Overexpression of miR-200b/429 mimics, ZEB1, and ZEB2 regulates contraction-associated genes and human myometrial cell contractility. S2). 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. Preterm labor was induced either by a single s.c. injection of the antiprogestin/antiglucocorticosteroid RU486 (15) (Fig. Because of their critical importance for species survival, the mechanisms whereby P4 and its nuclear receptor (PR) maintain myometrial quiescence during pregnancy, and for the … ↵*This Direct Submission article had a prearranged editor. 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 … (A) Diagram depicting P4 injection of mice in late gestation. hsa, Homo sapiens. We further demonstrated that ZEB1 is directly up-regulated by the action of progesterone (P4)/PR at the ZEB1 promoter. (C) ZEB1 but not ZEB2 mRNA is significantly increased by P4 treatment (same samples as in B). 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. The resulting elevated miRNAs can then feed back and repress both ZEB1 and ZEB2 (Fig. To this end, we conducted temporal expression analyses of CXN-43 and OXTR in the same myometrial samples used for analyses of miR-200b/429, ZEB1, and ZEB2. 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 … 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. 2019 Jul 1;25(7):408-422. doi: 10.1093/molehr/gaz028. 1F). 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. and C.R.M. 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/. S1B). 3F). Data are representative of three similar experiments. Minireview: Fetal-maternal hormonal signaling in pregnancy and labor, Progesterone withdrawal and estrogen activation in human parturition are coordinated by progesterone receptor A expression in the myometrium, A decline in the levels of progesterone receptor coactivators in the pregnant uterus at term may antagonize progesterone receptor function and contribute to the initiation of parturition, Term labor is associated with a core inflammatory response in human fetal membranes, myometrium, and cervix, Negative interaction between the RelA(p65) subunit of NF-kappaB and the progesterone receptor, Progesterone receptor plays a major antiinflammatory role in human myometrial cells by antagonism of nuclear factor-kappaB activation of cyclooxygenase 2 expression, MicroRNA regulation of cyclooxygenase-2 during embryo implantation, MicroRNAs are necessary for vascular smooth muscle growth, differentiation, and function, Discovery of novel microRNAs in female reproductive tract using next generation sequencing, The miR-200 family determines the epithelial phenotype of cancer cells by targeting the E-cadherin repressors ZEB1 and ZEB2, MicroRNA targeting specificity in mammals: Determinants beyond seed pairing, miR-200b mediates post-transcriptional repression of ZFHX1B, The miR-200 family inhibits epithelial-mesenchymal transition and cancer cell migration by direct targeting of E-cadherin transcriptional repressors ZEB1 and ZEB2, The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1, RU486 (mifepristone): Mechanisms of action and clinical uses, Bacteria-induced or bacterial product-induced preterm parturition in mice and rabbits is preceded by a significant fall in serum progesterone concentrations, A double-negative feedback loop between ZEB1-SIP1 and the microRNA-200 family regulates epithelial-mesenchymal transition, A reciprocal repression between ZEB1 and members of the miR-200 family promotes EMT and invasion in cancer cells, Telomerase immortalization of human myometrial cells, ZEB represses transcription through interaction with the corepressor CtBP, Fibroblast mechanics in 3D collagen matrices, Contraction of cultured human uterine smooth muscle cells after stimulation with endothelin-1, Modulation of human uterine smooth muscle cell collagen contractility by thrombin, Y-27632, TNF alpha and indomethacin, Surfactant protein secreted by the maturing mouse fetal lung acts as a hormone that signals the initiation of parturition, Integration of endocrine and mechanical signals in the regulation of myometrial functions during pregnancy and labour, Serum progesterone levels in the pregnant and postpartum laboratory mouse, Ablation of connexin43 in uterine smooth muscle cells of the mouse causes delayed parturition, Oxytocin is required for nursing but is not essential for parturition or reproductive behavior, Pervasive social deficits, but normal parturition, in oxytocin receptor-deficient mice, Induction of preterm birth in mice by RU486, Expression of Zfhep/deltaEF1 protein in palate, neural progenitors, and differentiated neurons, Regulation of c-fos expression by static stretch in rat myometrial smooth muscle cells, Proceedings of the National Academy of Sciences, Earth, Atmospheric, and Planetary Sciences, www.pnas.org/lookup/suppl/doi:10.1073/pnas.1008301107/-/DCSupplemental, Science & Culture: At the nexus of music and medicine, some see disease treatments, News Feature: Tracing gold's cosmic origins, Journal Club: Friends appear to share patterns of brain activity, Transplantation of sperm-producing stem cells. 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). 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. In fertile women, directed unilateral transport of immotile sperm-like material through the genital tract to the side bearing the dominant follicle can be assessed using hysterosalping… 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. 2B). None of the vehicle-injected mice delivered preterm. Thus, it is the balance between uterine stress-mediated activation of non-apoptotic CASP3 and augmented adaptive UPR signaling that facilitates quiescence. Female mice were housed with male mice overnight beginning at 1800 hours. Mean ± SEM values are shown (Student’s t test, *P < 0.05; n = 14 for laboring myometrium, n = 23 for nonlaboring controls). was supported by the National Institutes of Health (Grant 5-P01-HD11149) and the March of Dimes Birth Defects Foundation (Grant 21-FY07-601). Astronomers thought they’d finally figured out where gold and other heavy elements in the universe came from. 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. (H) CXN-43 and OXTR in the same samples as in E and F were significantly up-regulated in laboring myometrium. The miR-200 family was found to be up-regulated (Fig.  |  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. 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. Experiments were repeated twice with similar results. Researchers are still trying to understand what causes this strong correlation between neural and social networks. 4A). Using a ChIP Assay Kit (catalog no. 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). This negative feedback loop, which is supported by the present findings in the pregnant mouse and human myometrium and in cultured human myometrial cells as well as by published reports by others (17, 18), results in further induction of contraction-associated gene expression and labor. contributed new reagents/analytic tools; N.E.R. 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