2022年 · 第04卷第01期

Objective: This study aimed at investigating the expression of nuclear factor kappa B (NF-κB) and mammalian target of rapamycin (mTOR) related signal pathways in liver tissues of intrahepatic cholestasis of pregnancy animal models. Methods: Estrogen (EE)-induced cholestasis and a placental ischemia-reperfusion (IR) model were established in pregnant rats. All pregnant rats were divided into four groups by random number table: EE-IR group (n= 6), EE-sham group (n = 6), control-IR group (n= 6) and control-sham group (n= 6). Liver expression of mTOR, its upstream regulator DNA damage response-1 (REDD1), and downstream factor glucose transporter type-1 (GLUT1), accompanied by NF-κB (p65 is the most important component), its activator toll-like receptor 4 (TLR4), and inhibitor IκBα, were detected by western blot analysis and real-time polymerase chain reaction. The intergroup comparisons were performed with a one-way analysis of variance, the comparisons among groups were analyzed with the nonparametric Kruskal-Wallis test. Results: Giving pregnant rats EE alone reduced the hepatic expression of IκBα (0.72 ± 0.20 vs. 1.01 ± 0.07, P= 0.008). Meanwhile, giving pregnant rats placental IR alone increased liver levels of REDD1 (3.24 ± 0.98 vs. 1.06 ± 0.24, P= 0.025), GLUT1 (2.37 ± 0.82 vs. 1.09 ± 0.10, P= 0.039), TLR4 (2.12 ± 0.29 vs. 1.20 ± 0.28, P= 0.010), and p65 (2.09 ± 0.85 vs. 1.04 ± 0.06, P= 0.023), and decreased hepatic mTOR (0.50 ± 0.07 vs. 1.01 ± 0.03, P= 0.001) and IκBα (0.61 ± 0.08 vs. 1.01 ± 0.07, P= 0.014) expression. Subjecting EE-treated rats to placental IR did not further alter liver levels of GLUT1 (2.02 ± 0.45 vs. 1.79 ± 0.39, P= 0.240), TLR4 (2.10 ± 0.74 vs. 1.60 ± 0.36, P= 0.129), or p65 (2.41 ± 0.83 vs. 1.65 ± 0.46, P= 0.145), whereas it did decrease hepatic mTOR (0.42 ± 0.09 vs. 0.90 ± 0.14, P= 0.008) and IκBα (0.43 ± 0.09 vs. 0.72 ± 0.20, P= 0.004) expression and enhance REDD1 expression (4.46 ± 0.65 vs. 2.05 ± 0.47, P= 0.009). Placental IR stress did impact the hepatic expression of REDD1-mTOR-GLUT1 and TLR4/NF-κB/IκBα in pregnant rats. Conclusion: Placental IR-induced hepatic GLUT1, TLR4, and p65 alternation, which responded efficiently in control rats, were impaired in EE-induced ICP rats.

Objective: To investigate the possible regulatory mechanism of corticotropin-releasing hormone (CRH), urocortin (UCN), and Wolfram syndrome 1 (WFS1) in 17α-ethynylestradiol (EE)-induced intrahepatic cholestasis pregnant rats and its ischemia reperfusion (IR) model. Methods: Pregnant rats (n=60) were randomly divided into four experimental groups by random number table (Control, EE, IR, and EE-IR groups),and were studied on the 17th, 19th, and 21st gestational days (GD) (n=5 in each group at the indicated time). Growth and development indicators of fetal rats among these four groups were recorded. Enzyme-linked immunosorbent assay was employed to detect CRH, UCN, and WFS1 levels in maternal sera. Western blotting and real-time polymerase chain reaction were used to quantify placental protein and placental mRNA levels of CRH, UCN, and WFS1. Multivariate analysis of variance and least significant difference test were used to establish the group and individual comparisons. Results: A significant difference was found in placenta weight (F=8.10, P<0.05), fetal rat weight (F=40.86, P<0.05), fetal rat length (F=61.61, P<0.05), and fetal rat tail length (F=55.63, P<0.05) among four groups on the 17th ,19th , and 21st GD.What’s more, the overall differences of maternal serum UCN levels among Control, EE, IR, and EE-IR groups were significant (F=2.48, P<0.05). Expression of WFS1 mRNA in the EE-IR group was significantly increased and higher than Control (0.46±0.15 vs. 0.24±0.09, P<0.05), EE (0.46±0.15 vs. 0.17±0.04, P>0.05), and IR (0.46±0.15 vs. 0.22±0.15, P>0.05) groups at 19th GD, indicating that endoplasmic reticulum stress may be activated. However, the expression of CRH (0.42±0.05 vs. 0.58±0.12, P<0.05), UCN (0.43±0.01 vs. 0.47±0.16, P>0.05), and WFS1 (0.57±0.07 vs. 0.74±0.12, P>0.05) protein in the EE-IR group was subsided compared to the IR group at 17th GD. Conclusion: Fetal rat growth restriction was found in the EE-induced intrahepatic cholestasis model. This study revealed that significant changes in the maternal sera level of UCN , placental level of WFS1 mRNA and placental levels of CRH, UCN, and WFS1 protein in chronic versus acute stress in a rat model of pregnancy. This suggests an impaired compensatory vasodilatory effect mediated by these factors at gene transcription and protein translation levels, following acute hypoxia stress in EE-induced intrahepatic cholestasis in pregnant rats.

Decidualization is the differentiation of endometrial stromal cells into secretory decidual stromal cells. Human decidualization involves some amount of signaling molecules and pathways as well as genetic reprogramming, which is driven by the postovulatory rise in progesterone levels and local cyclic adenosine monophosphate production. Decidualization extends from the primary decidual zone to the secondary decidual zone, and then exits through apoptosis. Evidences support that decidual fibroblasts function as the pool of decidual stromal cells during pregnancy. Decidualization undergoes an acute inflammatory phase, an anti-inflammatory secretory phase to the final recession phase. The decidualization of the inner layer of endometrium, termed decidua, is the most critical determinant of pregnancy success, which can promote placenta formation, modulate immune tolerance, foster resistance to oxidative stress, sense embryo quality, and control labor. Failure to adequate decidualization in terms of hormones, biochemistry, and immunology leads to adverse pregnancy outcomes, including diseases such as preeclampsia, miscarriage, premature labor, repeated implantation failures, and some age-related decline in reproductive capacity. The development of animal models and in vitro culture systems combined with emerging technologies provides a powerful system to explore the mechanism of decidualization. However, decidualization is a dynamic, multi-step process, and translating of current research progress into disease predictions and interventions for pregnancy complications remains to be achieved. The study of periodic regeneration and spontaneous decidualization of the endometrium will be beneficial to the diagnosis and treatment of pregnancy diseases.

Serving as the interface between the fetal and maternal environments during gestation, the placenta plays critical roles in the protection of the developing fetus and the maintenance of maternal health. The placenta is primarily derived from the embryonic trophectoderm which differentiates into various subtypes of trophoblast cells through villous and extravillous pathways. The interactions among trophoblasts and multiple decidual cells and immune cells at the maternal-fetal interface fundamentally form the functional units of the placenta, which are responsible for blood perfusion and maternal-fetal material exchange, immune tolerance, and the regulation of pregnancy adaptation. Defects in placental development and functional maintenance are in tight association with adverse pregnancy outcomes such as preeclampsia. In this article, we review recent advances on human trophoblast cell differentiation and the construction of placental functional units and discuss the placental and maternal factors that may contribute to the occurrence of preeclampsia.

Normal pregnancy is associated with dramatically increased estrogen biosynthesis whose role is believed to raise uterine blood flow to facilitate the bi-directional maternal-fetal exchanges of gases (O2 and CO2), to deliver nutrients, and exhaust wastes to support fetal development and survival. Constrained uterine blood flow in pregnancy is a leading cause of preeclampsia with fetal growth restriction, rendering investigations of uterine hemodynamics to hold a high promise to inform pathways as targets for therapeutic interventions for preeclampsia. The mechanisms of estrogen-induced uterine vasodilation in pregnancy have long been attributed to enhanced endothelium production of nitric oxide, but clinical trials targeting this pathway that dominates uterine hemodynamics have achieved no to little success. Emerging evidence has recently shown a novel proangiogenic vasodilatory role of hydrogen sulfide in regulating uterine hemodynamics in pregnancy and preeclampsia, provoking a new field of perinatal research in searching for alternative pathways for pregnancy disorders especially preeclampsia and intrauterine growth restriction. This minireview is intended to summarize the nitric oxide pathway and to discuss the emerging hydrogen sulfide pathway in modulating estrogen-induced uterine vasodilation in pregnancy and preeclampsia.

Preterm labor (before 37 weeks’ gestation) is the leading cause of neonatal mortality and morbidity, which can be divided into iatrogenic preterm labor, infectious preterm labor, and spontaneous preterm labor (sPTL). Up to now, there continue to be great difficulties in prediction and prevention of sPTL, owing to multiple risk factors, pathogenesis, and pathologic processes contributing to the event, which have not been fully clarified. Pregnancy maintenance and parturition is a complicated process with continuous maternal-fetal dialogue, in which both maternal and fetal factors participate and affect the outcome of pregnancy, including sPTL. Besides, external factors can also participate in sPTL, individually or through the interaction with internal factors. In this article, we summarize recent studies regarding sPTL from our and other groups, and discuss the risk factors and pathogenesis of preterm birth from both external and internal (maternal and fetal) aspects, so as to provide theoretical evidences for the diagnosis, prevention, and treatment of sPTL in the future.

Viral infections during pregnancy are associated with adverse pregnancy outcomes, including maternal and fetal mortality, pregnancy loss, premature labor, and congenital anomalies. Mammalian gestation encounters an immunological paradox wherein the placenta balances the tolerance of an allogeneic fetus with protection against pathogens. Viruses cannot easily transmit from mother to fetus due to physical and immunological barriers at the maternal-fetal interface posing a restricted threat to the fetus and newborns. Despite this, the unknown strategies utilized by certain viruses could weaken the placental barrier to trigger severe maternal and fetal health issues especially through vertical transmission, which was not fully understood until now. In this review, we summarize diverse aspects of the major viral infections relevant to pregnancy, including the characteristics of pathogenesis, related maternal-fetal complications, and the underlying molecular and cellular mechanisms of vertical transmission. We highlight the fundamental signatures of complex placental defense mechanisms, which will prepare us to fight the next emerging and re-emerging infectious disease in the pregnancy population.