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Uterine Notch2 facilitates pregnancy recognition and corpus luteum maintenance via upregulating decidual Prl8a2.

ABSTRACT: The maternal recognition of pregnancy is a necessary prerequisite for gestation maintenance through prolonging the corpus luteum lifespan and ensuring progesterone production. In addition to pituitary prolactin and placental lactogens, decidual derived prolactin family members have been presumed to possess luteotropic effect. However, there was a lack of convincing evidence to support this hypothesis. Here, we unveiled an essential role of uterine Notch2 in pregnancy recognition and corpus luteum maintenance. Uterine-specific deletion of Notch2 did not affect female fertility. Nevertheless, the expression of decidual Prl8a2, a member of the prolactin family, was downregulated due to Notch2 ablation. Subsequently, we interrupted pituitary prolactin function to determine the luteotropic role of the decidua by employing the lipopolysaccharide-induced prolactin resistance model, or blocking the prolactin signaling by prolactin receptor-Fc fusion protein, or repressing pituitary prolactin release by dopamine receptor agonist bromocriptine, and found that Notch2-deficient females were more sensitive to these stresses and ended up in pregnancy loss resulting from abnormal corpus luteum function and insufficient serum progesterone level. Overexpression of Prl8a2 in Notch2 knockout mice rescued lipopolysaccharide-induced abortion, highlighting its luteotropic function. Further investigation adopting Rbpj knockout and DNMAML overexpression mouse models along with chromatin immunoprecipitation assay and luciferase analysis confirmed that Prl8a2 was regulated by the canonical Notch signaling. Collectively, our findings demonstrated that decidual prolactin members, under the control of uterine Notch signaling, assisted pituitary prolactin to sustain corpus luteum function and serum progesterone level during post-implantation phase, which was conducive to pregnancy recognition and maintenance.

SUBMITTER: Bao H

PROVIDER: S-EPMC8432799 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background: Nowadays, frozen-thawed embryo transfer (FET) cycles represent a high proportion of fertility treatments worldwide. Recent studies suggest differences in pregnancy outcomes depending on the FET treatment protocol used. The reason for this is still unclear, but the number of corpora lutea (CL) at conception is discussed as a possible factor. This study aims to investigate whether maternal and neonatal outcomes for pregnancies following FET lacking a CL differ from FET with one or more CL in order to explore a potential link between CL absence and adverse pregnancy outcomes. Methods: The study was designed as a retrospective, multi-center observational study with two cohorts after singleton live birth [0 CL cohort (FET in a programmed cycle, n = 114) and ≥ 1 CL cohort (FET in a natural or stimulated cycle, n = 68)]. Participants completed a questionnaire on the outcome of pregnancy and birth records were analyzed in a descriptive way. Multivariable logistic and linear regressions were performed in order to explore associations between CL absence and pregnancy outcomes. The strength of the agreement between the information in the survey and the diagnoses extracted from the files was assessed by Cohen's Kappa. Results: The risk of hypertensive disorders of pregnancy was higher after FET in the absence of a CL compared to FET with CL presence (aOR 5.56, 95% CI 1.12 - 27.72). Birthweights and birthweight percentiles were significantly higher in the 0 CL group. CL absence was a predictor of higher birthweight (adjusted coefficient B 179.74, 95% CI 13.03 - 346.44) and higher birthweight percentiles (adjusted coefficient B 10.23, 95%, 95% CI 2.28 - 18.40) particularly in female newborns of the 0 CL cohort. While the strength of the agreement between the reported information in the survey and the actual diagnoses extracted from the files was good for the majority of outcomes of interest it was fair in terms of hypertension (κ = 0.38). Conclusion: This study supports observations suggesting a potential link between a lack of CL at conception and adverse maternal and neonatal outcomes. Further investigations on causes and pathophysiological relationships are yet to be conducted.

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Uterine Notch2 facilitates pregnancy recognition and corpus luteum maintenance via upregulating decidual Prl8a2.

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