Decidual Cox2 inhibition improves fetal and maternal outcomes in a preeclampsia-like mouse model.
Ontology highlight
ABSTRACT:
SUBMITTER: Sones JL
PROVIDER: S-EPMC4855694 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:The mechanisms leading to worse outcomes in African-American (AA) women with preeclampsia/eclampsia remain unclear. Our objective was to identify racial differences in maternal comorbidities, peripartum characteristics, and maternal and fetal outcomes.When compared to white women with preeclampsia/eclampsia, AA women had an increased unadjusted risk of inpatient maternal mortality (OR 3.70, 95% CI: 2.19-6.24). After adjustment for covariates, in-hospital mortality for AA women remained higher than that for white women (OR 2.85, 95% CI: 1.38-5.53), while the adjusted risk of death among Hispanic women did not differ from that for white women. We also found an increased risk of intrauterine fetal death (IUFD) among AA women. When compared to white women with preeclampsia, AA women had an increased unadjusted odds of IUFD (OR 2.78, 95% CI: 2.49-3.11), which remained significant after adjustment for covariates (adjusted OR 2.45, 95% CI: 2.14-2.82). In contrast, IUFD among Hispanic women did not differ from that for white women after adjusting for covariates.Our data suggest that African-American women are more likely to have risk factors for preeclampsia and more likely to suffer an adverse outcome during peripartum care. Future research should examine whether controlling co-morbidities and other risk factors will help to alleviate racial disparities in outcomes in this cohort of women.
| S-EPMC4782921 | biostudies-literature
Project description:BackgroundThis study was conducted to evaluate how the preeclampsia integrated estimate of risk (fullPIERS) model performs in the prediction of adverse maternal outcomes when the predictor variables are all obtained within 24-h of admission for preeclampsia.MethodsA prospective cohort study on 323 women who fulfilled definite inclusion and exclusion criteria was conducted. Subjects were monitored for clinical symptoms of preeclampsia, biochemical parameters, and adverse maternal and neonatal outcomes. A risk prediction score was calculated using the fullPIERS calculator. Statistical analysis of rates and ratios was carried out by assessing ? (2) test and odds ratio.Results18.3 % (n = 60) had adverse maternal outcome and 42.8 % (n = 138) had adverse fetal outcome, and 43 (13.35 %) had combined adverse maternal and perinatal outcome. Dyspnea, visual disturbances, epigastric pain, and [Formula: see text] appeared to be highly significant risk factors. In the biochemical variables studied, serum creatinine and serum uric acid were found to have a significant association. The association between adverse perinatal outcome and vaginal delivery was highly significant (OR 0.35, 95 % CI 0.19, 0.63), and the P value was 0.0005. The likelihood ratio associated with the highest risk group (predicted probability of the outcome ?30 %) showed excellent performance (i.e., 17.5) of fullPIERS model as a rule in test.ConclusionThe fullPIERS model performed well in the prediction of adverse maternal outcomes in women with preeclampsia. It is easy to use. The model is based on the use of few important clinical and biochemical parameters and does not require extensive laboratory testing. Although it might be of limited use in a well-equipped tertiary care facility, this model can be utilized in the setting of district or sub-district level hospitals to identify patients who are at risk of complications due to preeclampsia. Timely referral to a higher center will help in reducing the morbidity and mortality associated with this condition.
| S-EPMC5016414 | biostudies-literature
Project description:ObjectiveTo examine whether maternal race could affect the relationship between fetal sex and preeclampsia.Material and methodsThis study was a cohort analysis using prospectively collected data from pregnant women who participated in the Vitamin Antenatal Asthma Reduction Trial (VDAART). Preeclampsia was the secondary outcome of VDAART. We examined the association of fetal sex with preeclampsia and its potential interaction with maternal race in 813 pregnant women (8% with preeclampsia) in logistic regression models with adjustment for preterm birth (<37 weeks of gestation), maternal age, education, and body mass index at enrollment and clinical center. We further conducted a race stratified analysis and also examined whether any observed association was dependent on the gestational age at delivery and prematurity.ResultsIn an analysis of all races combined, preeclampsia was not more common among pregnant women with a male fetus compared to those with a female fetus (odds ratio [OR] = 1.3, 95% CI = 0.81, 2.24). There was an interaction between African American race and fetal sex in association with preeclampsia after adjustment for preterm delivery and other potential confounders (p = .014). In race stratified analyses, we observed higher odds of preeclampsia among African American pregnant women who carried male fetuses after adjustment for preterm delivery and other potential confounders (adjusted OR = 2.4, 95% CI = 1.12, 5.60).ConclusionWe observed fetal sexual dimorphic differences in the occurrence of preeclampsia in African American women, but not in Whites. Information on fetal sex may ultimately improve the prediction of pre-eclampsia in African American mothers, who might be at higher risk for this adverse condition in pregnancy.
| S-EPMC7954987 | biostudies-literature
Project description:Preeclampsia is a cardiovascular pregnancy complication characterised by new onset hypertension and organ damage or intrauterine growth restriction. It is one of the leading causes of maternal and fetal mortality in pregnancy globally. Short of pre-term delivery of the fetus and placenta, treatment options are limited. Consequently, preeclampsia leads to increased cardiovascular disease risk in both mothers and offspring later in life. Here we aim to examine the impact of the reduced uterine perfusion pressure (RUPP) rat model of preeclampsia on the maternal cardiovascular system, placental and fetal heart metabolism. The surgical RUPP model was induced in pregnant rats by applying silver clips around the aorta and uterine arteries on gestational day 14, resulting in ~ 40% uterine blood flow reduction. The experiment was terminated on gestational day 19 and metabolomic profile of placentae, maternal and fetal hearts analysed using high-resolution 1H NMR spectroscopy. Impairment of uterine perfusion in RUPP rats caused placental and cardiac hypoxia and a series of metabolic adaptations: altered energetics, carbohydrate, lipid and amino acid metabolism of placentae and maternal hearts. Comparatively, the fetal metabolic phenotype was mildly affected. Nevertheless, long-term effects of these changes in both mothers and the offspring should be investigated further in the future.
| S-EPMC8782944 | biostudies-literature
Project description:Preeclampsia (PE) and fetal growth restriction (FGR) are both placenta-mediated disorders with unclear pathogenesis. Metabolomics of maternal and fetal pairs might help in understanding these disorders. We recruited prospectively pregnancies with normotensive FGR, PE without FGR, PE + FGR and uncomplicated pregnancies as controls. Nuclear magnetic resonance metabolomics were applied on plasma samples collected at delivery. Advanced lipoprotein, glycoprotein and choline profiling was performed using the Liposcale test. The software package Dolphin was used to quantify 24 low-molecular-weight metabolites. Statistical analysis comprised the comparison between each group of complicated pregnancies versus controls, considering 5% false discovery rate correction. Lipid profiles were altered in accordance with the clinical presentation of these disorders. Specifically, PE mothers and FGR fetuses (with or without FGR or PE, respectively) exhibited a pro-atherogenic and pro-inflammatory profile, with higher concentrations of triglycerides, remnant cholesterol (VLDL, IDL) and Glc/GalNAc-linked and lipid-associated glycoproteins compared to controls. Low-molecular-weight metabolites were extensively disturbed in preeclamptic mothers, with or without FGR. Growth restricted fetuses in the presence of PE showed changes in low-molecular-weight metabolites similar to their mothers (increased creatine and creatinine), while normotensive FGR fetuses presented scarce differences, consistent with undernutrition (lower isoleucine). Further research is warranted to clarify maternal and fetal adaptations to PE and FGR.
| S-EPMC8277896 | biostudies-literature
Project description:Rationale & objectivesPreeclampsia, which disproportionately affects Black women, is a leading cause of preterm delivery and risk for future hypertension and chronic kidney disease (CKD). Apolipoprotein L1 (APOL1) kidney risk alleles, common among Black individuals, contribute substantially to CKD disparities. Given the strong link between preeclampsia and CKD, we investigated whether maternal and fetal APOL1 risk alleles can jointly influence preeclampsia risk, and explored potential modifiers of the association between APOL1 and preeclampsia.Study designNested case-control study.Setting & participants426 Black mother-infant pairs (275 African Americans and 151 Haitians) from the Boston Birth Cohort.ExposureMaternal and fetal APOL1 risk alleles.OutcomesPreeclampsia.Analytical approachLogistic regression models with adjustment for demographic characteristics were applied to analyze associations between fetal and maternal APOL1 risk alleles and risk of preeclampsia and to investigate the effects of modification by maternal country of origin.ResultsFetal APOL1 risk alleles tended to be associated with an increased risk of preeclampsia, which was not statistically significant in the total genotyped population. However, this association was modified by maternal country of origin (P<0.05 for interaction tests): fetal APOL1 risk alleles were significantly associated with an increased risk of preeclampsia among African Americans under recessive (odds ratio [OR], 3.6 [95% CI, 1.3-9.7]; P=0.01) and additive (OR, 1.7 [95% CI, 1.1-2.6]; P=0.01) genetic models but not in Haitian Americans. Also, maternal-fetal genotype discordance at the APOL1 locus was associated with a 2.6-fold higher risk of preeclampsia (P<0.001) in African Americans.LimitationsLimited sample size in stratified analyses; self-reported maternal country of origin; pre-pregnancy estimated glomerular filtration rate (eGFR) and proteinuria data in mothers were not collected; unmeasured confounding social and/or environmental factors; no replication study.ConclusionsThis study supports the hypothesis that fetal APOL1 kidney risk alleles are associated with increased risk for preeclampsia in a recessive mode of inheritance in African Americans and suggests that maternal-fetal genotype discordance is also associated with this risk. These conclusions underscore the need to better understand maternal-fetal interaction and their genetic and environmental factors as contributors to ethnic disparities in preeclampsia.
| S-EPMC8351532 | biostudies-literature
Project description: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.
| S-EPMC8149889 | biostudies-literature
Project description:Inhibition of hepatocyte growth factor (HGF)/c-MET pathway, a major mediator of pancreatic stellate cell (PSC)-PC cell interactions, retards local and distant cancer progression. This study examines the use of this treatment in preventing PC progression after resection. We further investigate the postulated existence of circulating PSCs (cPSCs) as a mediator of metastatic PC. Two orthotopic PC mouse models, produced by implantation of a mixture of luciferase-tagged human pancreatic cancer cells (AsPC-1), and human PSCs were used. Model 1 mice underwent distal pancreatectomy 3-weeks post-implantation (n = 62). One-week post-resection, mice were randomised to four treatments of 8 weeks: (i) IgG, (ii) gemcitabine (G), (iii) HGF/c-MET inhibition (HiCi) and (iv) HiCi + G. Tumour burden was assessed longitudinally by bioluminescence. Circulating tumour cells and cPSCs were enriched by filtration. Tumours of Model 2 mice progressed for 8 weeks prior to the collection of primary tumour, metastases and blood for single-cell RNA-sequencing (scRNA-seq). HiCi treatments: (1) reduced both the risk and rate of disease progression after resection; (2) demonstrated an anti-angiogenic effect on immunohistochemistry; (3) reduced cPSC counts. cPSCs were identified using immunocytochemistry (α-smooth muscle actin+, pan-cytokeratin-, CD45-), and by specific PSC markers. scRNA-seq confirmed the existence of cPSCs and identified potential genes associated with development into cPSCs. This study is the first to demonstrate the efficacy of adjuvant HGF/c-Met inhibition for PC and provides the first confirmation of the existence of circulating PSCs.
| S-EPMC8199621 | biostudies-literature
Project description:Preeclampsia affects ∼2-8% of pregnancies worldwide. It is associated with increased long-term maternal cardiovascular disease risk. This study assesses the effect of the vasoconstrictor N(ω)-nitro-L-arginine methyl ester (L-NAME) in modelling preeclampsia in mice, and its long-term effects on maternal cardiovascular health. In this study, we found that L-NAME administration mimicked key characteristics of preeclampsia, including elevated blood pressure, impaired fetal and placental growth, and increased circulating endothelin-1 (vasoconstrictor), soluble fms-like tyrosine kinase-1 (anti-angiogenic factor), and C-reactive protein (inflammatory marker). Post-delivery, mice that received L-NAME in pregnancy recovered, with no discernible changes in measured cardiovascular indices at 1-, 2-, and 4-wk post-delivery, compared with matched controls. At 10-wk post-delivery, arteries collected from the L-NAME mice constricted significantly more to phenylephrine than controls. In addition, these mice had increased kidney Mmp9:Timp1 and heart Tnf mRNA expression, indicating increased inflammation. These findings suggest that though administration of L-NAME in mice certainly models key characteristics of preeclampsia during pregnancy, it does not appear to model the adverse increase in cardiovascular disease risk seen in individuals after preeclampsia.
| S-EPMC9356384 | biostudies-literature
Project description:Utero-placental development in pregnancy depends on direct maternal-fetal interaction in the uterine wall decidua. Abnormal uterine vascular remodeling preceding placental oxidative stress and placental dysfunction are associated with preeclampsia and fetal growth restriction (FGR). Oxidative stress is counteracted by antioxidants and oxidative repair mechanisms regulated by the transcription factor nuclear factor erythroid 2-related factor 2 (NRF2). We aimed to determine the decidual regulation of the oxidative-stress response by NRF2 and its negative regulator Kelch-like ECH-associated protein 1 (KEAP1) in normal pregnancies and preeclamptic pregnancies with and without FGR. Decidual tissue from 145 pregnancies at delivery was assessed for oxidative stress, non-enzymatic antioxidant capacity, cellular NRF2- and KEAP1-protein expression, and NRF2-regulated transcriptional activation. Preeclampsia combined with FGR was associated with an increased oxidative-stress level and NRF2-regulated gene expression in the decidua, while decidual NRF2- and KEAP1-protein expression was unaffected. Although preeclampsia with normal fetal growth also showed increased decidual oxidative stress, NRF2-regulated gene expression was reduced, and KEAP1-protein expression was increased in areas of high trophoblast density. The trophoblast-dependent KEAP1-protein expression in preeclampsia with normal fetal growth indicates control of decidual oxidative stress by maternal-fetal interaction and underscores the importance of discriminating between preeclampsia with and without FGR.
| S-EPMC8875334 | biostudies-literature