Gestational weight gain of multiparas and risk of primary preeclampsia: a retrospective cohort study in Shanghai.

BACKGROUND: In all studies conducted so far, there was no report about the correlation between excessive gestational weight gain (GWG) and the risk of preeclampsia (PE) in multiparas, especially considering that multiparity is a protective factor for both excessive GWG and PE. Thus, the aim of this retrospective cohort study was to determine whether GWG of multiparas is associated with the increased risk of PE. METHODS: This was a study with 15,541 multiparous women who delivered in a maternity hospital in Shanghai from 2017 to 2021, stratified by early-pregnancy body mass index (BMI) category. Early-pregnancy body weight, height, week-specific and total gestational weight gain as well as records of antenatal care were extracted using electronic medical records, and antenatal weight gain measurements were standardized into gestational age-specific z scores. RESULTS: Among these 15,541 multiparous women, 534 (3.44%) developed preeclampsia. The odds of preeclampsia increased by 26% with every 1 z score increase in pregnancy weight gain among normal weight women and by 41% among overweight or obese women. For normal weight women, pregnant women with preeclampsia gained more weight than pregnant women without preeclampsia beginning at 25 weeks of gestation, while accelerated weight gain was more obvious in overweight or obese women after 25 weeks of gestation. CONCLUSIONS: In conclusion, excessive GWG in normal weight and overweight or obese multiparas was strongly associated with the increased risk of preeclampsia. In parallel, the appropriate management and control of weight gain, especially in the second and third trimesters, may lower the risk of developing preeclampsia.

miR-4443/MMP2 suppresses the migration and invasion of trophoblasts through the HB-EGF/EGFR pathway in preeclampsia.

Preeclampsia (PE) is a pregnancy-associated disease that may cause maternal and fetal morbidity and mortality. The dysregulation of microRNAs (miRNAs) and their potential functions has been an important direction for elucidating the mechanism of preeclampsia in recent years. The present study investigated whether miR-4443 was significantly increased in the placentas of severe preeclamptic patients, and the upregulation of miR-4443 inhibited the migration and invasion of HTR-8/SVneo cells according to transwell assays. Matrix metallopeptidase 2 (MMP2), which is involved in the degradation of extracellular matrix (ECM) components and harbors a miR-4443-binding site within its 3'-UTR as confirmed by a luciferase reporter assay, was identified to be directly inhibited by miR-4443. Moreover, siRNA targeting MMP2 imitated the effects of overexpressed miR-4443 on HTR-8/SVneo cell invasion and migration, whereas rescue experiments showed that MMP2 reversed this inhibitory function of miR-4443. Heparin-binding EGF-like growth factor (HB-EGF), as the downstream gene of MMP2, plays an important role in trophoblast invasion, and we confirmed that the expression of HB-EGF/EGFR pathway-related biomolecules was consistent with MMP2 influenced by upregulating and downregulating miR-4443 and that activated EGFR further transmitted intracellular downstream signaling via the MAPK pathway according to western blot assay. In conclusion, we demonstrated that miR-4443 suppresses the migration and invasion of trophoblasts, and its inhibitory effects are at least partially mediated by the suppression of MMP2. This inhibition might further affect the progression of preeclampsia through the HB-EGF/EGFR pathway, thus providing a new clue on the role of miR-4443 in the pathogenesis of preeclampsia.

Autophagy Activation by Hypoxia Regulates Angiogenesis and Apoptosis in Oxidized Low-Density Lipoprotein-Induced Preeclampsia.

Objective: Autophagy influences a wide range of physiological and pathological processes in the human body. In this study, we aimed to investigate the role of autophagy in early-onset preeclampsia (EOPE); autophagy activation by hypoxia could rescue impaired angiogenesis and apoptosis in preeclampsia, leading by ox-LDL. Methods: Transmission electron microscopy was applied to identify autolysosomes in trophoblast cells of the placenta apical region. Quantitative real-time polymerase chain reaction, Western blot, flow cytometry, and wound-healing assays were adopted to determine autophagy activity, angiogenesis, and apoptosis in placenta tissues or HTR8/SVneo cells. Results: Autophagy activity was inhibited in the placenta of women who experienced EOPE; autophagy activation by hypoxia enhanced the migration ability, rescued ox-LDL-mediated impaired angiogenesis in HTR8/SVneo cells [vascular endothelial growth factor A (VEGFA) downregulation and FMS-like tyrosine kinase-1 (FLT1) upregulation], and protected against cell apoptosis (BAX downregulation). Conclusion: Autophagy could maintain the function of trophoblast cells by differentially regulating the expression of VEGFA and FLT1 and protecting against cell apoptosis at the maternal-fetal interface, potentially related to prevention of preeclampsia.

Identification of mRNA-, circRNA- and lncRNA- Associated ceRNA Networks and Potential Biomarkers for Preeclampsia From Umbilical Vein Endothelial Cells.

OBJECTIVE: The etiology and pathogenesis of preeclampsia (PE) remain unclear, and ideal biomarkers for the early detection of PE are scarce. The involvement of the competing endogenous RNA (ceRNA) hypothesis in PE is only partially understood. The present study aimed to delineate a regulatory network in PE comprised of messenger RNAs (mRNAs), circular RNAs (circRNAs), long non-coding RNAs (lncRNAs), and microRNAs (miRNAs) via ceRNA profiles from human umbilical vein endothelial cells (HUVECs) to further reveal the pathogenesis of PE and potential biomarkers. METHODS: Differentially expressed mRNAs, circRNAs, and lncRNAs were detected in HUVECs from early onset preeclampsia (EOPE) cases (n = 4) and normal pregnancies (n = 4) by microarray analysis. Bioinformatics analysis was performed to systematically analyze the data, and a relevant ceRNA network was constructed. RNAs (ANGPT2, LIPG, hsa_circ_0025992, hsa_circ_0090396, hsa_circ_0066955, hsa_circ_0041203, hsa_circ_0018116, lnc-C17orf64-1:1, lnc-SLC27A2-2:1, and lnc-UEVLD-5:1) were validated by quantitative real-time PCR (qRT-PCR) in 10 pairs of HUVECs and placental tissues from PE patients and normal pregnancies. Furthermore, expression of hsa_circ_0025992 was detected in maternal peripheral blood samples from PE patients (n = 24) and normal pregnancies (n = 30) to confirm its potential as a novel biomarker. The receiver operating characteristic (ROC) curve was applied to analyze its diagnostic value. RESULTS: Compared with HUVECs from normal pregnancies, HUVECs from EOPE cases had 33 differentially expressed mRNAs (DEmRNAs), 272 DEcircRNAs, and 207 DElncRNAs. GO and KEGG analyses of the DERNAs revealed the biological processes and pathways involved in PE. Based on the microarray data and the predicted miRNAs, a ceRNA network was constructed with four mRNAs, 34 circRNAs, nine lncRNAs, and 99 miRNAs. GO and KEGG analyses of the network reinforced the crucial roles of metabolic disorders, the p53 and JAK/STAT signaling pathways in PE. In addition, ROC analysis indicated that hsa_circ_0025992 could be used as a novel biomarker for PE. CONCLUSION: A novel ceRNA network was revealed in PE, and the potential of hsa_circ_0025992 to serve as a new biomarker was confirmed.

NRP1 and MMP9 are dual targets of RNA-binding protein QKI5 to alter VEGF-R/ NRP1 signalling in trophoblasts in preeclampsia.

Preeclampsia (PE) is characterized by placental ischemia and hypoxia, resulting in abnormal casting of the uterine spiral artery, which is mainly caused by insufficient trophoblastic cell infiltration. A reduction in levels of growth factor-based signalling via Neuropilin-1 (NRP1) has been shown to contribute to dysfunctional trophoblast development. In this study, we showed that the RNA-binding protein, QKI5, regulated NRP1 expression and significantly improved trophoblast proliferation in vitro and in vivo. QKI5 and NRP1 expressions were significantly reduced in human PE placentas and in trophoblasts during hypoxia. Overexpression of these factors significantly improved cell proliferation and migration in vitro, in contrast to a decrease upon siRNA knockdown of QKI5 and NRP1 in HTR-8/SVneo cells. Using RIP and RNA pull-down assays, we further showed that QKI5 directly interacted with the 3'-UTR region of NRP1, to mediate cell proliferation and migration via matrix metalloprotease-9. Further, similar to NRP1, QKI5 also targets matrix metalloproteinase 9 (MMP9) involved in secretion of growth factors and its effects can be counteracted by NRP1 overexpression. In vivo studies using a PE mouse model revealed that QKI5 overexpression alleviated PE-related symptoms such as elevated blood pressure and proteinuria. Taken together, we found that QKI5 was a novel regulator, of VEGF-R/NRP1 signalling pathway functioning in trophoblast proliferation and migration, resulting in major contributors to the pathogenesis of PE. While careful evaluation of the broad implications of QKI5 expression is still necessary, this study identified QKI5 as a promising target for treatment strategies in acute PE patients.

Recombinant chromosome 4 in two fetuses - case report and literature review.

BACKGROUND: Recombinant chromosome 4 syndrome (rec 4 syndrome) is a rare genetic disorder, predominately resulting from a parental pericentric inversion of chromosome 4. To date, a total of 18 cases of rec (4) syndrome were published in literature. We report the first kindred of rec (4) syndrome analyzed using copy number variation sequencing (CNV-seq). RESULTS: A woman with two adverse fetal outcomes was described in the present study. The first fetus presented with severe intrauterine growth restriction, hyposarca, hydrothorax and ascites. The CNV-seq revealed a dup 4q and del 4p. The second fetus presented with cardiovascular disease of ventricular septal defect, overriding aorta and persistent trunk. The CNV-seq revealed a dup 4p and del 4q. We collected 18 rec (4) cases through literature review. Genotype-phenotype correlation analysis was also performed. CONCLUSION: Recombinant 4 syndrome is a rare genetic disorder. It should be divided into two categories according to the alternative recombinant types. The clinical manifestations of rec (4) cases with dup 4q and del 4p are consistent with the Wolf-Hirschhorn syndrome. For cases harboring dup 4p and del 4q, the high incidence of congenital heart disease is prominent.

TLR9 (Toll-Like Receptor 9) Agonist Suppresses Angiogenesis by Differentially Regulating VEGFA (Vascular Endothelial Growth Factor A) and sFLT1 (Soluble Vascular Endothelial Growth Factor Receptor 1) in Preeclampsia.

Preeclampsia is a common pregnancy-specific disorder characterized by elevated blood pressure and proteinuria. Activation of the maternal immune system and impaired placental angiogenesis are thought to contribute to the pathogenesis of preeclampsia. TLR9 (Toll-like receptor 9) plays a role in innate immunity, defending the organism against infection. The purpose of this study was to determine whether TLR9 inhibits angiogenesis at the fetomaternal interface under conditions of preeclampsia. We confirmed the downregulation of VEGFA (vascular endothelial growth factor A) and upregulation of TLR9 and sFLT1 (soluble vascular endothelial growth factor receptor 1) in placentas from preeclamptic women. Then, we established a mouse model with preeclampsia-like symptoms using the synthetic TLR9 agonist CpG (cytidine-phosphate-guanosine)-ODN (oligodeoxynucleotide; ODN1826). We observed the downregulation of VEGFA and the upregulation of sFLT1 in placentas from the preeclampsia-like animal model and in trophoblasts treated with CpG-ODN (ODN2006). In addition, silencing TLR9 promoted the migration and invasion of HTR8/SVneo cells. In conclusion, TLR9 is capable of robustly suppressing angiogenesis by differentially regulating the expression of VEGFA and sFLT1 at the fetomaternal interface, potentially contributing to the development of preeclampsia.

Associations of lipid levels during gestation with hypertensive disorders of pregnancy and gestational diabetes mellitus: a prospective longitudinal cohort study.

OBJECTIVE: To assess associations of elevated lipid levels during gestation with hypertensive disorders of pregnancy (HDP) and gestational diabetes mellitus (GDM). METHODS: This prospective cohort study was conducted in a tertiary maternal hospital in Shanghai, China from February to November 2014. Lipid constituents, including triglycerides (TGs), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-c) and high-density lipoprotein cholesterol (HDL-c) of 1310 eligible women were assessed in the first (10-13+ weeks), second (22-28 weeks) and third (30-35 weeks) trimesters consecutively. Associations of lipid profiles with HDP and/or GDM outcomes were assessed. RESULTS: Compared with the normal group, maternal TG concentrations were higher in the HDP/GDM groups across the three trimesters (p<0.001); TC and LDL-c amounts were only higher in the first trimester for the HDP and GDM groups (p<0.05). HDL-c levels were similar in the three groups. Compared with intermediate TG levels (25-75th centile), higher TG amounts (>75th centile) were associated with increased risk of HDP/GDM in each trimester with aORs (95% CI) of 2.04 (1.41 to 2.95), 1.81 (1.25 to 2.63) and 1.78 (1.24 to 2.54), respectively. High TG elevation from the first to third trimesters (>75th centile) was associated with increased risk of HDP, with an aOR of 2.09 (1.16 to 3.78). High TG elevation before 28 weeks was associated with increased risk of GDM, with an aOR of 1.67 (1.10 to 2.54). TG elevation was positively correlated with weight gain during gestation (R=0.089, p=0.005). CONCLUSIONS: Controlling weight gain during pregnancy could decrease TG elevation and reduce the risk of HDP/GDM. TGs could be used as follow-up parameters during complicated pregnancy, while other lipids are meaningful only in the first trimester.

Human endometrial mesenchymal stem cells exhibit intrinsic anti-tumor properties on human epithelial ovarian cancer cells.

Epithelial ovarian cancer (EOC) is the most lethal tumor of all gynecologic tumors. There is no curative therapy for EOC thus far. The tumor-homing ability of adult mesenchymal stem cells (MSCs) provide the promising potential to use them as vehicles to transport therapeutic agents to the site of tumor. Meanwhile, studies have showed the intrinsic anti-tumor properties of MSCs against various kinds of cancer, including epithelial ovarian cancer. Human endometrial mesenchymal stem cells (EnSCs) derived from menstrual blood are a novel source for adult MSCs and exert restorative function in some diseases. Whether EnSCs endow innate anti-tumor properties on EOC cells has never been reported. By using tumor-bearing animal model and ex vivo experiments, we found that EnSCs attenuated tumor growth by inducing cell cycle arrest, promoting apoptosis, disturbing mitochondria membrane potential and decreasing pro-angiogenic ability in EOC cells in vitro and/or in vivo. Furthermore, EnSCs decreased AKT phosphorylation and promoted nuclear translocation of Forkhead box O-3a (FoxO3a) in EOC cells. Collectively, our findings elucidated the potential intrinsic anti-tumor properties of EnSCs on EOC cells in vivo and in vitro. This research provides a potential strategy for EnSC-based anti-cancer therapy against epithelial ovarian cancer.