Prostaglandin Mediates Premature Delivery in Pregnant Sheep Induced by Estradiol at 121 Days of Gestational Age

Wen, Wu; Xiao, Hong; Coksaygan, Turhan; Chakrabarty, K; Collins, Valta; Rose, James C.; Nathanielsz, Peter W.

doi:10.1210/en.2003-1142

Cited by 31 publications

(40 citation statements)

References 32 publications

(49 reference statements)

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“…Although estrogens are known to induce myometrial contractions and labor in animal species such as the sheep (Wu et al 2004) and to promote the expression and/or function of contraction-associated proteins in human myometrial smooth muscle cells (Di et al 2001, Knock et al 2001, the genomic targets and signaling pathways controlled by estrogens in the pregnant uterus are poorly understood. Considering the importance of estrogen sensitivity in regulating the contractile capacity of the myometrium, it is surprising that ER expression in the human pregnant myometrium has not been systematically characterized.…”

Section: Discussionmentioning

confidence: 99%

Estrogen receptor (ER) expression and function in the pregnant human myometrium: estradiol via ERα activates ERK1/2 signaling in term myometrium

Welsh

Johnson

et al. 2011

Journal of Endocrinology

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Estrogens are thought to promote labor by increasing the expression of pro-contraction genes in myometrial cells. The specific estrogen receptors ((ERs: ERa and ERb (also known as ESR1 and ESR2)) and G protein-coupled receptor 30 (GPR30; also known as G protein-coupled estrogen receptor 1)) and signaling pathways that mediate these actions are not clearly understood. In this study, we identified the ERs expressed in the pregnant human myometrium and determined a key extranuclear signaling pathway through which estradiol (E 2 ) modulates expression of the gene encoding the oxytocin receptor (OXTR), a major pro-contraction protein. Using quantitative RT-PCR, we found that ERa and GPR30 mRNAs were expressed in the human pregnant myometrium while ERb mRNA was virtually undetectable. While mRNA encoding ERa was the predominant ER transcript in the pregnant myometrium, ERa protein was largely undetectable in myometrial tissue by immunoblotting. Pharmacological inhibition of 26S proteasome activity increased ERa protein abundance to detectable levels in term myometrial explants, however, indicating rapid turnover of ERa protein by proteasomal processing in the pregnant myometrium. E 2 stimulated rapid extranuclear signaling in myometrial explants, as evidenced by increased extracellularly regulated kinase (ERK1/2) phosphorylation within 10 min. This effect was inhibited by pre-treatment with an ER antagonist, ICI 182 780, indicating the involvement of ERa. Inhibition of ERK signaling abrogated the ability of E 2 to stimulate OXTR gene expression in myometrial explants. We conclude that estrogenic actions in the human myometrium during pregnancy, including the stimulation of contraction-associated gene expression, can be mediated by extranuclear signaling through ERa via activation of the ERK/mitogen-activated protein kinase pathway.

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Section: Discussionmentioning

confidence: 99%

Estrogen receptor (ER) expression and function in the pregnant human myometrium: estradiol via ERα activates ERK1/2 signaling in term myometrium

Welsh

Johnson

et al. 2011

Journal of Endocrinology

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“…Treatments that initiate premature delivery, also induce the characteristic increase in PGF secretion from the uterus before luteolysis and parturition (Wu et al, 2004). Inhibition of PGF production by treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) will delay or prevent luteolysis near parturition (Jenkin, 1992;Sugimoto et al, 1998;Jenkin and Young, 2004).…”

Section: Period IV Parturition-induced Luteolysis-day 270-290 Of Prementioning

confidence: 99%

Maintenance or regression of the corpus luteum during multiple decisive periods of bovinepregnancy

Wiltbank¹,

Meidan²,

Ochoa³

et al. 2016

Anim Reprod

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In ruminants, there are specific times during the estrous cycle or pregnancy when the corpus luteum (CL) may undergo regression. This review has attempted to summarize the physiological and cellular mechanisms involved in CL regression or maintenance during four distinct periods. The first period is near day 7 when animals that are ovulating after a period of low circulating progesterone (P4), such as first pubertal ovulation or first postpartum ovulation, are at risk of having a premature increase in Prostaglandin F2α (PGF) secreted from the uterus resulting in early CL regression and a short estrous cycle. The second period is when normal luteolysis occurs at day 18-25 of the cycle or when the CL is rescued by interferon-tau secreted by the elongating embryo. The uterine mechanisms that determine the timing of this luteolysis or the prevention of luteolysis have been generally defined. Induction and activation of endometrial E2 receptors result in induction of endometrial oxytocin receptors that can now be activated by normal pulses of oxytocin. Of particular importance is the observation that the primary mechanisms are only activated through local (ipsilateral) and not a systemic route due to transfer of PGF from the uterine vein to the ovarian artery. In addition at the CL level, studies are providing definition to the cellular and molecular mechanisms that are activated in response to uterine PGF pulses or pregnancy. The third period that is discussed occurs in the second month of pregnancy (day 28-60) when undefined mechanisms result in CL maintenance of an ipsilateral CL but regression of a contralateral (opposite side from pregnancy) CL. The final period that is discussed is regression of the CL just prior to parturition. Although, cortisol from the fetus appears to be the primary initiator of luteolysis, PGF seems to be the final signal that causes regression of the CL. Thus, in all four periods, regression of the CL is likely to be caused by the direct actions of PGF that is secreted from the uterus. The uterine mechanisms that result in secretion of PGF seem to be normally inhibited during the early luteal phase, making short luteal phases not a normal event, and are altered during early pregnancy (day 18-25) resulting in prevention of luteolysis. During much of pregnancy, the mechanisms that cause PGF secretion from the uterus in response to oxytocin are intact but luteolysis does not normally occur, perhaps due to lack of efficient utero-ovarian transfer of PGF.

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“…We intentionally set the animal experiment at a time point in gestation before the increase in fetal cortisol takes place. The fetal and maternal carotid arterial catheters were implanted as we described previously (Wu et al 2004a). Maternal and fetal arterial blood samples were taken daily for the determination of pH and blood gases to evaluate maternal and fetal well-being.…”

Section: Animals and Tissue Collectionmentioning

confidence: 99%

Separate and synergistic effect of progesterone and estradiol on induction of annexin 2 and its interaction protein p11 in pregnant sheep myometrium

Zhang

Wen

2007

Journal of Molecular Endocrinology

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To search for myometrial candidate genes regulated by progesterone, we isolated annexin 2 cDNA by subtractive hybridization and cloning. We also examined the effect of estradiol and/or progesterone, individually or combined, on expressions of annexin 2 and its ligand protein, p11 in pregnant sheep intrauterine tissues. Annexin 2 is a Ca 2C -dependent phospholipid-binding protein which interacts with p11 to form a bivalent heterotetramer. The heterotetramer was indicated in the production of prostaglandins through the regulation of cytosolic phospholipase A2 (cPLA2) and arachidonic acid release. Thus, annexin 2 and p11 could be the important players in Ca 2C signaling and prostaglandin production in uterine smooth muscles. Twenty-two ewes were treated with vehicle (nZ6), or 5 mg estradiol administered intramuscularly twice a day for 2 days (nZ6), or 100 mg progesterone administered intramuscularly twice a day for 14 days (nZ5), or estradiol plus progesterone with 100 mg progesterone administered intramuscularly twice a day for 10 days (nZ5) and then with vehicle for 2 days followed by estradiol for 2 days (5 mg administered intramuscularly twice a day). At 121 days of gestation age (dGA), endometrium, myometrium, placenta, and cervix were obtained under halothane anesthesia. Subtractive hybridization was used to isolate differentially expressed mRNAs from myometrial tissues treated with progesterone, which was confirmed by western blot at protein level. Annexin 2 and p11 interaction was validated by immunoprecipitation and their expressions in intrauterine tissues were determined by western blot analysis. Data were analyzed by ANOVA. A cDNA clone from myometrial-subtracted library representing differentially expressed mRNA in the pregnant sheep myometrium with progesterone treatment was identified as annexin 2 by sequence analysis and BLASTN search. Annexin 2 was present in both cytosolic and membrane-associated fractions of intrauterine tissues. In contrast, p11 was detectable only in myometrial cytosolic fraction. Both annexin 2 and p11 significantly increased in myometrial cytosolic fraction after progesterone or progesterone plus estradiol treatment. Furthermore, estradiol and progesterone combined had a more profound effect on induction of annexin 2 than progesterone alone. Annexin 2 was immunoprecipitated specifically by p11 antibody from the myometrium. This study indicates that progesterone may play an important role in the control of myometrial contractility by modifying protein expression associated with Ca 2C and prostaglandin signaling systems during pregnancy. Enhanced expression of myometrial annexin 2 in progesterone plus estradiol group supports our hypothesis that estrogen's stimulation is optimized by progesterone's priming in the pregnant sheep uterus.

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Prostaglandin Mediates Premature Delivery in Pregnant Sheep Induced by Estradiol at 121 Days of Gestational Age

Cited by 31 publications

References 32 publications

Estrogen receptor (ER) expression and function in the pregnant human myometrium: estradiol via ERα activates ERK1/2 signaling in term myometrium

Estrogen receptor (ER) expression and function in the pregnant human myometrium: estradiol via ERα activates ERK1/2 signaling in term myometrium

Maintenance or regression of the corpus luteum during multiple decisive periods of bovinepregnancy

Separate and synergistic effect of progesterone and estradiol on induction of annexin 2 and its interaction protein p11 in pregnant sheep myometrium

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