Pregnancy-associated Diseases Research Articles

The association between pulse wave velocity and pregnancy-associated diseases: A systematic review and meta-analysis

BackgroundMaintaining healthy vascular structure and function is important for a healthy pregnancy. Obesity is a well-known predictor for poor postoperative outcomes of vascular surgery. However, the association between pulse wave velocity (PWV), a well-recognized parameter for arterial stiffness assessment, and pregnancy-associated diseases is still unclear. Therefore, we conducted this systematic review, and a meta-analysis was performed to assess the relevant associations. MethodsWe systematically searched the Web of Science and PubMed databases to obtain articles on PWV and pregnancy-associated diseases published before April 2023. The mean with standard deviation was used to assess the differences in PWV in pregnant women with or without relevant diseases. Subgroup analysis was conducted according to specific types of PWV. The Newcastle‒Ottawa Scale was used to evaluate the quality of the enrolled studies. ResultsA total of 6488 individuals from 21 studies were included. All enrolled studies were high-quality. Overall, the PWV was elevated in pregnant women who suffered from preeclampsia (mean difference (MD) = 0.67, 95 % confidence interval (CI): 0.51,0.83, P < 0.00001), hypertension (MD = 1.04, 95 % CI: 1.00,1.08, P < 0.00001), gestational diabetes mellitus (MD = 0.34, 95%CI: 0.19,0.48, P < 0.00001), and diabetes (MD = 0.49, 95%CI: 0.27,0.70, P < 0.00001). Subgroup analysis based on specific types of PWV showed similar results. ConclusionIn our study, PWV is elevated in pregnancy-associated diseases, including preeclampsia, hypertension, and diabetes. The PWV assessment should be regarded as a clinical routine for pregnant women to prevent and manage cardiovascular diseases during pregnancy.

Trophoblast-derived miR-410-5p induces M2 macrophage polarization and mediates immunotolerance at the fetal-maternal interface by targeting the STAT1 signaling pathway

BackgroundMacrophages phenotypic deviation and immune imbalance play vital roles in pregnancy-associated diseases such as spontaneous miscarriage. Trophoblasts regulate phenotypic changes in macrophages, however, their underlying mechanism during pregnancy remains unclear. Therefore, this study aimed to elucidate the potential function of trophoblast-derived miRNAs (miR-410-5p) in macrophage polarization during pregnancy.MethodsPatient decidual macrophage tissue samples in spontaneous abortion group and normal pregnancy group (those who had induced abortion for non-medical reasons) were collected at the Reproductive Medicine Center of Renmin Hospital of Wuhan University from April to December 2021. Furthermore, placental villi and decidua tissue samples were collected from patients who had experienced a spontaneous miscarriage and normal pregnant women for validation and subsequent experiments at the Shenzhen Zhongshan Obstetrics & Gynecology Hospital (formerly Shenzhen Zhongshan Urology Hospital), from March 2021 to September 2022. As an animal model, 36 female mice were randomly divided into six groups as follows: naive-control, lipopolysaccharide-model, agomir-negative control prevention, agomir-410-5p prevention, agomir-negative control treatment, and agomir-410-5p treatment groups. We analyzed the miR-410-5p expression in abortion tissue and plasma samples; and supplemented miR-410-5p to evaluate embryonic absorption in vivo. The main source of miR-410-5p at the maternal–fetal interface was analyzed, and the possible target gene, signal transducer and activator of transcription (STAT) 1, of miR-410-5p was predicted. The effect of miR-410-5p and STAT1 regulation on macrophage phenotype, oxidative metabolism, and mitochondrial membrane potential was analyzed in vitro.ResultsMiR-410-5p levels were lower in the spontaneous abortion group compared with the normal pregnancy group, and plasma miR-410-5p levels could predict pregnancy and spontaneous abortion. Prophylactic supplementation of miR-410-5p in pregnant mice reduced lipopolysaccharide-mediated embryonic absorption and downregulated the decidual macrophage pro-inflammatory phenotype. MiR-410-5p were mainly distributed in villi, and trophoblasts secreted exosomes-miR-410-5p at the maternal–fetal interface. After macrophages captured exosomes, the cells shifted to the tolerance phenotype. STAT1 was a potential target gene of miR-410-5p. MiR-410-5p bound to STAT1 mRNA, and inhibited the expression of STAT1 protein. STAT1 can drive macrophages to mature to a pro-inflammatory phenotype. MiR-410-5p competitive silencing of STAT1 can avoid macrophage immune disorders.ConclusionMiR-410-5p promotes M2 macrophage polarization by inhibiting STAT1, thus ensuring a healthy pregnancy. These findings are of great significance for diagnosing and preventing spontaneous miscarriage, providing a new perspective for further research in this field.

Memory regulatory T cells in pregnancy.

Pregnancy requires the process of maternal immune tolerance to semi-allogeneic embryos. In contrast, an overreactive maternal immune system to embryo-specific antigens is likely to result in the rejection of embryos while damaging the invading placenta, such that the likelihood of adverse pregnancy outcomes can be increased. Regulatory T cells (Tregs) are capable of suppressing excessive immune responses and regulating immune homeostasis. When stimulating Tregs, specific antigens will differentiate into memory Tregs with long-term survival and rapid and powerful immune regulatory ability. Immunomodulatory effects mediated by memory Tregs at the maternal-fetal interface take on critical significance in a successful pregnancy. The impaired function of memory Tregs shows a correlation with various pregnancy complications (e.g., preeclampsia, gestational diabetes mellitus, and recurrent pregnancy losses). However, the differentiation process and characteristics of memory Tregs, especially their role in pregnancy, remain unclear. In this study, a review is presented in terms of memory Tregs differentiation and activation, the characteristics of memory Tregs and their role in pregnancy, and the correlation between memory Tregs and pregnancy complications. Furthermore, several potential therapeutic methods are investigated to restore the function of memory Tregs in accordance with immunopathologies arising from memory Tregs abnormalities and provide novel targets for diagnosing and treating pregnancy-associated diseases.

Maternal hepatic immunology during pregnancy.

The liver plays pivotal roles in immunologic responses, and correct hepatic adaptations in maternal immunology are required during pregnancy. In this review, we focus on anatomical and immunological maternal hepatic adaptations during pregnancy, including our recent reports in this area. Moreover, we summarize maternal pregnancy-associated liver diseases, including hyperemesis gravidarum; intrahepatic cholestasis of pregnancy; preeclampsia, specifically hemolysis, elevated liver enzymes, and low platelet count syndrome; and acute fatty liver of pregnancy. In addition, the latest information about the factors that regulate hepatic immunology during pregnancy are reviewed for the first time, including human chorionic gonadotropin, estrogen, progesterone, growth hormone, insulin like growth factor 1, oxytocin, adrenocorticotropic hormone, adrenal hormone, prolactin, melatonin and prostaglandins. In summary, the latest progress on maternal hepatic anatomy and immunological adaptations, maternal pregnancy-associated diseases and the factors that regulate hepatic immunology during pregnancy are discussed, which may be used to prevent embryo loss and abortion, as well as pregnancy-associated liver diseases.

A prospective study of myeloperoxidase levels in water immersion

IntroductionWe aimed to compare myeloperoxidase levels in cord blood samples of mothers undergoing water immersion or conventional labor. MethodWe enrolled 52 pregnant women to this case control study meeting the following criteria: uneventful gestational follow-ups, no history of known chronic or pregnancy-associated diseases, cesarean section or uterine operation, BMI <29.9 kg/m2, single vertex presentation, normal fetal heart rate pattern, 37–41 weeks of gestation, estimated fetal weight of 2500–4000 g. The subjects were either undergoing immersion in water (n = 26) or conventional labor (n = 26) and their myeloperoxidase levels were measured from cord blood samples. ResultsThe mean age of the study population was 24.55 ± 4.9 years. The mean BMI and weight gain during pregnancy were 26.8 ± 2.7 kg/m2 and 11.6 ± 5.3 kg, respectively. The mean age of gestation at birth was 39.6 ± 1.1 weeks, with a mean birth weight of 3205.5 ± 433.2 g. The subjects in water immersion and conventional labor groups showed no difference in terms of age, gestational age, BMI, and birth weight. The mean myeloperoxidase level was significantly lower in the water immersion group (759.8 ± 391.5 U/L) compared to that in the conventional labor group (1832.2 ± 1011.9 U/L, p = 0.004). DiscussionImmersion in water during the first stage of labor seems to be associated with low myeloperoxidase levels, suggesting reduced oxidative stress in this delivery method.

The effect of fetal hypoxia on myeloperoxidase levels in cord blood: a prospective study.

We aimed to compare myeloperoxidase (MPO) levels in cord blood samples of mothers with and without perinatal hypoxia, since fetal hypoxia results in decreased pH, base excess, and an increase in pCO<inf>2</inf> and lactate levels. We enrolled 42 pregnant women to this cross-sectional analytic study if they had met following criteria: uneventful gestational follow-ups, no known chronic or pregnancy-associated diseases, a BMI of <29.9, a singleton pregnancy, those with pregnancy over 34 weeks. The exclusion criteria for the study and control groups were as follows: presence of multiple pregnancies, fetal abnormality, any disease diagnosed before or during antenatal follow-up e.g., diabetes, hypertension, thyroid dysfunction, uncontrolled endocrine disease or abnormal kidney function, autoimmune disease, chronic inflammatory diseases, IUGR, preeclampsia), maternal age below 18 or above 35, intrauterine exitus, pregnancy with assisted reproductive technique, alcohol or smoking addiction, and any chronic drug use. The subjects were 1:1 randomized to either hypoxic newborns (N.=21) and those in the control group (N.=21) and their myeloperoxidase levels were measured from cord blood samples. Results were expressed as U/L. Patient data regarding age, gestation, parity, birth weight, birth length, APGAR scores, and neonatal complications were collected. All the women signed written informed consent forms and accepted verbal consent before being included in the study. The mean age of the study population was 26.9±5.3 years. The mean BMI was 28.3±3.5 kg/m2. For the hypoxic group, 21 newborns with cord blood below 7.25 were included in the study group. The bloods with pH above 7.25 formed the control group. Mean pH and five (5) minute APGAR scores were found to be significantly lower in the study group, while base excess (BE) was found to be significantly higher. In this study, we compared the MPO levels of hypoxic newborns and those in the control group, and we did not find a significant difference between the two groups (P=0.147). Pearson Correlation Analysis is at -0.566 with P value (0.008) showing significant negative correlation between MPO and pH in the study group. We found that MPO values are negatively correlated with cord blood pH among newborns diagnosed with fetal hypoxia.

Effect of Ezrin on regulating trophoblast cell invasion via PKC signaling pathway in unexplained recurrent spontaneous abortion

Trophoblast cells are the most important cells in early pregnancy and their invasion are essential to the establishment and maintenance of pregnancy. Inadequate trophoblast cell invasion has been closely associated with several pregnancy-associated diseases including recurrent spontaneous abortion (RSA). Ezrin is an actin-associated protein, known as a marker for carcinogenesis and metastasis in solid tumors, has been proposed to play a role in the formation of microvilli in the early embryo. To further characterize its function in early pregnancy, we explored the expression of Ezrin in the trophoblast cells in early pregnancy. In this study, compared with normal pregnant women, we demonstrated that the expression of Ezrin and phosphorylated Ezrin decreased in the trophoblast cells in unexplained RSA (URSA) patients, and knockdown of Ezrin expression could suppress the invasiveness of trophoblast cells significantly. Various studies indicated that the phosphorylation of Ezrin on C-terminal threonine residue (T567) is a key event in the regulation of its activity. Our further exploration indicated that Ezrin was activated via PKC pathway. Furthermore, inhibition of the PKC pathway by a specific inhibitor suppressed invasiveness of Bewo cells. On the other hand, activation of the PKC pathway could increase the relative capacity of trophoblast cell invasion, while Ezrin knockdown reversed PKC activation induced cell invasion. These findings might provide a new fundamental mechanism for successful pregnancy and new diagnostic and therapeutic target for RSA.

Placental Development and Pregnancy-Associated Diseases

Abstract 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.

Roles of Two Small Leucine-Rich Proteoglycans Decorin and Biglycan in Pregnancy and Pregnancy-Associated Diseases.

Two small leucine-rich proteoglycans (SLRP), decorin and biglycan, play important roles in structural–functional integrity of the placenta and fetal membranes, and their alterations can result in several pregnancy-associated diseases. In this review, we briefly discuss normal placental structure and functions, define and classify SLRPs, and then focus on two SLRPs, decorin (DCN) and biglycan (BGN). We discuss the consequences of deletions/mutations of DCN and BGN. We then summarize DCN and BGN expression in the pregnant uterus, myometrium, decidua, placenta, and fetal membranes. Actions of these SLRPs as ligands are then discussed in the context of multiple binding partners in the extracellular matrix and cell surface (receptors), as well as their alterations in pathological pregnancies, such as preeclampsia, fetal growth restriction, and preterm premature rupture of membranes. Lastly, we raise some unanswered questions as food for thought.

Influence of Pregnancy-Related Conditions on Human Epididymis Protein 4 Serum Levels in Comparison to CA125 - a Prospective Cohort Trial.

Introduction HE4 and CA 125, two established biomarkers for assessing adnexal masses in non-pregnant women, are hardly investigated in pregnancy, especially in pregnancy-associated conditions. The aim was to evaluate HE4 and CA 125 levels in the course of pregnancy and to assess the impact of pregnancy disorders, contractions and rupture of membranes on HE4 and CA 125 serum levels in order to use these parameters for evaluation of adnexal masses in pregnancy. Patients and Methods Blood samples (n = 238) of 201 women seen at the Medical University of Innsbruck, Austria, were prospectively obtained during pregnancy and postpartum. Serum concentrations of HE4 and CA 125 were analyzed. ROMA index was calculated by the premenopausal formula. Results HE4 serum levels were highest in the third trimester. Contractions (p < 0.001), rupture of membranes (p = 0.005) and pregnancy-associated diseases (p = 0.003) were associated with higher HE4 levels. As much as 97.5% of HE4 measurements remained below the recommended cut-off for premenopausal women (70 pmol/l). CA 125 levels were not altered by pregnancy-associated conditions. Generally, CA 125 exhibited a wider serum level variability, exceeding the established cut-off of 35 U/ml in 16.4%. Conclusions HE4 serum levels are influenced by several pregnancy-related conditions leading to significantly higher levels in these cases. Despite differing medians according to trimester, the 95th percentile cut-offs and almost all maximum values during the entire course of pregnancy were below the established cut-off for premenopausal women. It was also superior to the performance of ROMA index. Therefore, HE4 can be used as a valuable negative predictive marker for the assessment of adnexal masses during pregnancy.

Role of ARID1A in the Regulation of Human Trophoblast Migration and Invasion.

Migration and invasion of trophoblasts is critical for human placental development, trophoblastic differentiation, and pregnancy-associated diseases. AT-rich interactive domain-containing protein 1A (ARID1A), a subunit of the SWI-SNF complex, has been suggested to participate in the regulation of fertility via placental disruption in mice. However, whether ARID1A regulates human placental development and function remains unknown. Here, using human trophoblast-like JEG-3 cell line, we report that ARID1A controls trophoblast cell migration and invasion. Overexpression of ARID1A inhibits JEG-3 cell migration and invasion, whereas knockdown of ARID1A promotes migration and invasion in JEG-3 cells. Mechanistically, while ARID1A reduces JEG-3 cell migration by down-regulation of Snail transcription, it restrains JEG-3 cell invasion by binding to and destabilization of MMP-9 protein. Finally, ARID1A is apparently up-regulated in placental tissues of preeclampsia compared to that of normal pregnancies. Our results thereby imply that ARID1A acts as a critical gene in supporting the physiological function of human mature placenta.

The Role of microRNA Let-7d in Female Malignancies and Diseases of the Female Reproductive Tract.

microRNAs are small noncoding RNAs that regulate gene expression at the posttranscriptional level. Let-7d is a microRNA of the conserved let-7 family that is dysregulated in female malignancies including breast cancer, ovarian cancer, endometrial cancer, and cervical cancer. Moreover, a dysregulation is observed in endometriosis and pregnancy-associated diseases such as preeclampsia and fetal growth restriction. Let-7d expression is regulated by cytokines and steroids, involving transcriptional regulation by OCT4, MYC and p53, as well as posttranscriptional regulation via LIN28 and ADAR. By downregulating a wide range of relevant mRNA targets, let-7d affects cellular processes that drive disease progression such as cell proliferation, apoptosis (resistance), angiogenesis and immune cell function. In an oncological context, let-7d has a tumor-suppressive function, although some of its functions are context-dependent. Notably, its expression is associated with improved therapeutic responses to chemotherapy in breast and ovarian cancer. Studies in mouse models have furthermore revealed important roles in uterine development and function, with implications for obstetric diseases. Apart from a possible utility as a diagnostic blood-based biomarker, pharmacological modulation of let-7d emerges as a promising therapeutic concept in a variety of female disease conditions.

Decidual Natural Killer Cells: A Good Nanny at the Maternal-Fetal Interface During Early Pregnancy.

Decidual natural killer (dNK) cells are the tissue-resident and major subpopulation of NK cells at the maternal-fetal interface. It has been demonstrated that dNK cells play pivotal roles in pregnancy, including keeping maternal-fetal immune tolerance, promoting extravillous trophoblast (EVT) cell invasion, and driving uterine spiral artery remodeling. However, the molecular mechanisms haven’t been elucidated until recent years. In this review, we systemically introduce the generation, subsets, and surface or soluble molecules of dNK cells, which are critical for maintaining the functions of dNK cells. Further, new functions of dNK cells including well-controlled cytotoxicity, immunosurveillance and immunotrophism supporting via the cell-cell interaction between dNK cells and EVT cells are mainly focused. The molecular mechanisms involved in these functions are also illustrated. Moreover, pregnancy-associated diseases caused by the dNK cells abnormalities are discussed. It will be important for future investigations about the mechanism of maintenance of pregnancy and parturition and potential clinical applications of dNK cells.

Placenta-Derived Exosomes as a Modulator in Maternal Immune Tolerance During Pregnancy.

Exosomes are a subset of extracellular vesicles with an average diameter of ~100nm. Exosomes are released by all cells through an endosome-dependent pathway and carry nucleic acids, proteins, lipids, cytokines and metabolites, mirroring the state of the originating cells. The function of exosomes has been implicated in various reproduction processes, such as embryo development, implantation, decidualization and placentation. Placenta-derived exosomes (pEXO) can be detected in the maternal blood as early as 6 weeks after conception and their levels increase with gestational age. Importantly, alternations in the molecular signatures of pEXO are observed in pregnancy-related complications. Thus, these differentially expressed molecules could be the potential biomarkers for diagnosis of the pregnancy-associated diseases. Recent studies have demonstrated that pEXO play a key role in the establishment of maternal immune tolerance, which is critical for a successful pregnancy. To gain a better understanding of the underlying mechanism, we highlighted the advanced studies of pEXO on immune cells in pregnancy.

Human Placenta MicroRNA Differences Between First and Third Trimester

MiRNAs are widespread regulators of gene expression, and altered miRNA expression in the placenta may be involved in abnormal placentation and related pregnancy-associated diseases. It is essential to understand miRNA expression changes across gestation before miRNAs can be used as biomarkers or prognostic indicators. Using next-generation sequencing, we characterize the normative human placenta miRNA transcriptome in both the first and third trimester using leftover chorionic villus sampling tissue from prenatal tests (N=113) as well as placentae collected at delivery (N=47). We identified 2503 miRNAs, including 1647 with stable expression across gestation (p>=0.05). There were 775 significantly differentially expressed miRNAs (FDR<0.05), with 402 upregulated in first trimester and 373 upregulated in third trimester. We also examine expression of the placenta-specific miRNA clusters on chromosomes 14 and 19 which are important in pregnancy. We identified predicted targets with high confidence scores or experimental verification, then used these to identify enriched canonical biological pathways. Our study identified canonical pathways consistently targeted across gestation, including pathways regulating senescence, proliferation and growth factor signaling. We also identified differentially impacted pathways, including growth- and immune-mediated pathways. This work provides a rich atlas to direct functional studies investigating the epigenetic differences in first and third trimester placentae. We gratefully acknowledge support from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD091773) and the Ruth L. Kirschstein National Research Service Award (T32DK007770) of the National Institutes of Health.

Association between HOX Transcript Antisense RNA Single-Nucleotide Variants and Recurrent Implantation Failure.

Recurrent implantation failure (RIF) refers to the occurrence of more than two failed in vitro fertilization–embryo transfers (IVF-ETs) in the same individual. RIF can occur for many reasons, including embryo characteristics, immunological factors, and coagulation factors. Genetics can also contribute to RIF, with some single-nucleotide variants (SNVs) reported to be associated with RIF occurrence. We examined SNVs in a long non-coding RNA, homeobox (HOX) transcript antisense RNA (HOTAIR), which is known to affect cancer development. HOTAIR regulates epigenetic outcomes through histone modifications and chromatin remodeling. We recruited 155 female RIF patients and 330 healthy controls, and genotyped HOTAIR SNVs, including rs4759314, rs920778, rs7958904, and rs1899663, in all participants. Differences in these SNVs were compared between the patient and control groups. We identified significant differences in the occurrence of heterozygous genotypes and the dominant expression model for the rs1899663 and rs7958904 SNVs between RIF patients and control subjects. These HOTAIR variants were associated with serum hemoglobin (Hgb), luteinizing hormone (LH), total cholesterol (T. chol), and blood urea nitrogen (BUN) levels, as assessed by analysis of variance (ANOVA). We analyzed the four HOTAIR SNVs and found significant differences in haplotype patterns between RIF patients and healthy controls. The results of this study showed that HOTAIR is not only associated with the development of cancer but also with pregnancy-associated diseases. This study represents the first report showing that HOTAIR is correlated with RIF.

Prevalence of the methylenetetrahydrofolate reductase 677C>T polymorphism in the pregnant women of Yunnan Province, China.

Mutations in the methylenetetrahydrofolate reductase (MTHFR) gene can result in a reduced ability to utilize folic acid. The MTHFR 677C>T polymorphism in particular has been linked to both birth defects and pregnancy-associated diseases. This study aimed to evaluate the prevalence of the MTHFR 677C>T mutation among pregnant women in Yunnan Province so as to collect baseline data that may be utilized to guide folic acid supplementation efforts and to support related disease prevention programs. We retrospectively reviewed 3387 pregnant women from Yunnan Province. The MTHFR 677C>T polymorphism was identified using polymerase chain reaction (PCR) and DNA sequencing. In total, 1350 (39.9%) subjects were homozygous for the C allele (CC), 1540 (45.4%) subjects were heterozygous (CT), and 497 (14.7%) subjects were homozygous for the T allele (TT). The MTHFR 677C>T polymorphism was found to be present within the studied population, with ∼60% of these patients being either heterozygous or homozygous for the mutant allele and with an overall T allele frequency of 0.37. The frequency of the T allele was significantly higher among pregnant women with complications relative to women with healthy pregnancies, particularly among women <30 years old. As such, the maternal MTHFR 677C>T polymorphism may be a genetic risk factor associated with pregnancy complications and may help identify pregnant women at a high risk of such complications.

Galectin-9 regulates HTR8/SVneo function via JNK signaling.

To obtain a successful pregnancy, trophoblasts must provide a physical barrier, suppress maternal reactivity, produce immunosuppressive hormones locally, and enhance the production of blocking factors that are able to bind to several antigenic sites. Inadequate placental perfusion has been closely associated with several pregnancy-associated diseases. Galectin-9 (Gal-9) has a wide variety of regulatory functions in innate and adaptive immunity during infection, tumor growth, and organ transplantation. We utilized immortalized human first-trimester extravillous trophoblast cells (HTR8/SVneo) for our functional study and examined the effects of Gal-9 on apoptosis, cytokine production and angiogenesis of HTR8/SVneo cells. Gal-9 inhibited the apoptosis and IFN-γ and IL-17A production, promoted IL-4 production, and coordinated the crosstalk between HTR8/SVneo cells and human umbilical vein endothelial cells via its interaction with Tim-3. Blockade of JNK signaling inhibited Gal-9 activities in HTR8/SVneo cells. In addition, we detected a correlation between low levels of Gal-9 and spontaneous abortion. So Gal-9 could inhibit the apoptosis and proinflammatory cytokine expression, and promote the angiogenesis and IL-4 production in HTR8/SVneo cells via Tim-3 in a JNK dependent manner to help the maintenance of normal pregnancy. These findings possibly identify Gal-9 as a key regulator of trophoblast cells and suggest its potential as a biomarker and target for the treatment of recurrent pregnancy loss.

PDIA3 regulates trophoblast apoptosis and proliferation in preeclampsia via the MDM2/p53 pathway.

Protein disulfide isomerase 3 (PDIA3) is a chaperone protein that modulates the folding of newly synthesized glycoproteins, has isomerase and redox activity, and has been implicated in the pathogenesis of many diseases. However, the role of PDIA3 in pregnancy-associated diseases remains largely unknown. Our present study reveals a key role for PDIA3 in the biology of placental trophoblasts from women with preeclampsia (PE). Immunohistochemistry and Western blot analysis revealed that PDIA3 expression was decreased in villous trophoblasts from women with PE compared to normotensive pregnancies. Further, using a Cell Counting Kit-8 assay, flow cytometry, and 5-ethynyl-2'-deoxyuridine (EdU) staining, we found that siRNA-mediated PDIA3 knockdown significantly promoted apoptosis and inhibited proliferation in the HTR8/SVneo cell line, while overexpression of PDIA3 reversed these effects. Furthermore, RNA sequencing and Western blot analysis demonstrated that knockdown of PDIA3 inhibited MDM2 protein expression in HTR8 cells, concurrent with marked elevation of p53 and p21 expression. Conversely, overexpression of PDIA3 had the opposite effects. Immunohistochemistry and Western blot further revealed that MDM2 protein expression was downregulated and p21 was increased in trophoblasts of women with PE compared to women with normotensive pregnancies. Our findings indicate that PDIA3 expression is decreased in the trophoblasts of women with PE, and decreased PDIA3 induces trophoblast apoptosis and represses trophoblast proliferation through regulating the MDM2/p53/p21 pathway.

CXCL12 in normal and pathological pregnancies: A review.

The survival of allogeneic fetuses during pregnancy is a rather paradoxical phenomenon with a complex mechanism. Chemokine ligand12 (CXCL12) and its receptors CXC chemokine receptor (CXCR)4 and 7 are extensively found in placenta tissues and cells, including trophoblast cells, vascular endothelial cells, and decidual stromal and decidual immune cells (eg, NK cells and regulatory T cells). Evidence has illustrated that the CXClL12/CXCR4/CXCR7 axis could enhance the cross talk at the maternal-fetal interface through multiple processes, such as invasion and placental angiogenesis, which appears to be critical signaling components in placentation and fetal outcome. In addition, an increasing number of studies have demonstrated that the CXCL12/CXCR4/CXCR7 axis also stands out for its pleiotropic roles in several pregnancy-associated diseases (eg, recurrent spontaneous abortion (RSA), pre-eclampsia (PE), and preterm labor). In the present review, the different biological properties and signaling in physiological and pathological pregnancy conditions of CXCL12/CXCR4/CXCR7 axis were discussed, with the aim of obtaining a further understanding of the regulatory mechanisms and highlighting their potential as a target for therapeutic approaches.