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Differential activation of placental unfolded protein response pathways implies heterogeneity in causation of early- and late-onset pre-eclampsia.

ABSTRACT: Based on gestational age at diagnosis and/or delivery, pre-eclampsia (PE) is commonly divided into early-onset (<34 weeks) and late-onset (?34 weeks) forms. Recently, the distinction between 'placental' and 'maternal' causation has been proposed, with 'placental' cases being more frequently associated with early-onset and intrauterine growth restriction. To test whether molecular placental pathology varies according to clinical presentation, we investigated stress-signalling pathways, including unfolded protein response (UPR) pathways, MAPK stress pathways, heat-shock proteins and AMPK? in placentae delivered by caesarean section for clinical indications at different gestational ages. Controls included second-trimester, pre-term and normal-term placentae. BeWo cells were used to investigate how these pathways react to different severities of hypoxia-reoxygenation (H/R) and pro-inflammatory cytokines. Activation of placental UPR and stress-response pathways, including P-IRE1?, ATF6, XBP-1, GRP78 and GRP94, P-p38/p38 and HSP70, was higher in early-onset PE than in both late-onset PE and normotensive controls (NTCs), with a clear inflection around 34 weeks. Placentae from ? 34 weeks PE and NTC were indistinguishable. Levels of UPR signalling were similar between second-trimester and term controls, but were significantly higher in pre-term 'controls' delivered vaginally for chorioamnionitis and other conditions. Severe H/R (1/20% O2 ) induced equivalent activation of UPR pathways, including P-eIF2?, ATF6, P-IRE1?, GRP78 and GRP94, in BeWo cells. By contrast, the pro-inflammatory cytokines TNF? and IL-1? induced only mild activation of P-eIF2? and GRP78. AKT, a central regulator of cell proliferation, was reduced in the < 34 weeks PE placentae and severe H/R-treated cells, but not in other conditions. These findings provide the first molecular evidence that placental stress may contribute to the pathophysiology of early-onset pre-eclampsia, whereas that is unlikely to be the case in the late-onset form of the syndrome.

SUBMITTER: Yung HW

PROVIDER: S-EPMC4277692 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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Differential activation of placental unfolded protein response pathways implies heterogeneity in causation of early- and late-onset pre-eclampsia.

Yung Hong Wa HW Atkinson Daniel D Campion-Smith Tim T Olovsson Matts M Charnock-Jones D Stephen DS Burton Graham J GJ

The Journal of pathology 20140806 2

Based on gestational age at diagnosis and/or delivery, pre-eclampsia (PE) is commonly divided into early-onset (<34 weeks) and late-onset (≥34 weeks) forms. Recently, the distinction between 'placental' and 'maternal' causation has been proposed, with 'placental' cases being more frequently associated with early-onset and intrauterine growth restriction. To test whether molecular placental pathology varies according to clinical presentation, we investigated stress-signalling pathways, including ...[more]

PMID: 24931423

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Project description:BackgroundPre-eclampsia shares pathophysiology with intrauterine growth restriction.ObjectiveTo investigate whether delivery of a small for gestational age (SGA) infant in the 1st pregnancy increases the risk of early and late onset pre-eclampsia in the 2nd pregnancy. Conversely, we investigated whether pre-eclampsia in the 1st pregnancy impacts SGA risk in the 2nd pregnancy.Study designWe studied a cohort from the Dutch Perinatal Registry of 265,031 women with 1st and 2nd singleton pregnancies who delivered between 2000 and 2007. We analyzed 2nd pregnancy risks of early and late onset pre-eclampsia-defined by delivery before or after 34 gestational weeks-as well as SGA below the 5th and between the 5th and 10th percentiles risks with multivariable logistic regressions. Interaction terms between 1st pregnancy hypertension, pre-eclampsia, SGA, and delivery before or after 34 gestational weeks were included in the regressions.ResultsFirst pregnancy early onset pre-eclampsia increased risk of SGA <5th percentile (OR 2.1, 95% CI 1.7-2.7) in the 2nd pregnancy. Late onset pre-eclampsia increased the SGA <5th percentile marginally (OR 1.1, 95% CI 1.0-1.3). In the absence of 1st pregnancy hypertensive disorder, women who delivered an SGA infant in their 1st pregnancy were at increased risk of 2nd pregnancy late onset pre-eclampsia (SGA <5th: OR 2.05, 95% CI 1.58-2.66; SGA 5-10th: OR 1.39, 95% CI 1.01-1.93). Early onset 2nd pregnancy pre-eclampsia risk was also increased, but this was only statistically significant for women who delivered an SGA infant below the 5th percentile in the 1st pregnancy (SGA <5th: OR 2.44, 95% CI 1.19-5.00; SGA 5-10th: OR 1.69, 95% CI 0.68-4.24;).ConclusionWomen with 1st pregnancy early onset pre-eclampsia have increased risk of SGA <5th percentile in the 2nd pregnancy. SGA in the 1st pregnancy increases pre-eclampsia risk in the 2nd pregnancy even in the absence of hypertensive disorders in the 1st pregnancy, although absolute risks remain low. These findings strengthen the evidence base associating intrauterine growth restriction with early onset pre-eclampsia.

Project description:BackgroundPre-eclampsia (PE) is a major cause of maternal and perinatal morbidity and mortality worldwide. It is defined by new onset of hypertension and proteinuria after the 20th week of gestation and characterized by systemic exaggerated inflammatory response. D6 is a chemokines scavenger receptor that binds with high affinity CC chemokines, internalizes and targets the ligands for degradation. It is expressed in trophoblast-derived tissues and prevents excessive placenta leukocyte infiltration.The aim of this study was to investigate the expression and function of D6 in human placentae from pre-eclamptic and healthy pregnant women.Methods and resultsPlasma levels of D6-binding CC chemokines (CCL-2, CCL-3, CCL-4, CCL-7, CCL-11) and pro-inflammatory cytokines (IL-6, TNF-?, CRP) were analyzed in 37 healthy pregnant women and 38 patients with PE by multiplex bead assay. Higher circulating levels of CCL7, CCL11, IL-6, (p<0.0001) and CRP (p<0.05) were observed in PE women compared to controls. Levels of circulating CCL4 were decreased in PE (p<0.001), while no significant differences of CCL2, CCL3 or TNF-? levels were detected. Immunofluorescent staining of placental sections showed higher expression of D6 receptor in the PE syncytiotrophoblast. Confocal and Western blot (WB) analyses revealed a prevalent distribution of D6 in trophoblast cells membranes in PE. Increased activation of D6 intracellular pathway was observed by Western blot analyses of p-LIMK and p-cofilin in trophoblast cell lysates. D6 functional assays showed reduced scavenging of CCL2 in PE cells compared to controls. Since actin filaments spatial assembling is essential for D6 intracellular trafficking and scavenging activity, we investigated by confocal microscopy trophoblast cytoskeleton organization and we observed a dramatic disarrangement in PE compared to controls.Conclusionsour results suggest membrane distribution of D6 receptor on trophoblast cell membranes in PE, together with reduced functionality, probably due to cytoskeleton impairment.

Project description:ObjectiveA high ratio of soluble fms-like tyrosine kinase-1 (sFlt-1) to placental growth factor (PlGF) has been linked to pre-eclampsia (PE). We evaluated the sFlt-1/PlGF ratio as a predictive marker for early-onset PE in women at risk of PE.MethodsThis prospective, Spanish, multicenter study included pregnant women with a risk factor for PE, including intrauterine growth restriction, PE, eclampsia or hemolysis, elevated liver enzymes and low platelet count syndrome in previous pregnancy, pregestational diabetes or abnormal uterine artery Doppler. The primary objective was to show that the sFlt-1/PlGF ratio at 20, 24 and 28 weeks' gestation was predictive of early-onset PE (< 34 + 0 weeks). Serum sFlt-1 and PlGF were measured at 20, 24 and 28 weeks. Multivariate logistic regression was used to develop a predictive model.ResultsA total of 819 women were enrolled, of which 729 were suitable for analysis. Of these, 78 (10.7%) women developed PE (24 early onset and 54 late onset). Median sFlt-1/PlGF ratio at 20, 24 and 28 weeks was 6.3 (interquartile range (IQR), 4.1-9.3), 4.0 (IQR, 2.6-6.3) and 3.3 (IQR, 2.0-5.9), respectively, for women who did not develop PE (controls); 14.5 (IQR, 5.5-43.7), 18.4 (IQR, 8.2-57.9) and 51.9 (IQR, 11.5-145.6) for women with early-onset PE; and 6.7 (IQR, 4.6-9.9), 4.7 (IQR, 2.8-7.2) and 6.0 (IQR, 3.8-10.5) for women with late-onset PE. Compared with early-onset PE, the sFlt-1/PlGF ratio was significantly lower in controls (P < 0.001 at each timepoint) and in women with chronic hypertension (P < 0.001 at each timepoint), gestational hypertension (P < 0.001 at each timepoint) and late-onset PE (P < 0.001 at each timepoint). A prediction model for early-onset PE was developed, which included the sFlt-1/PlGF ratio plus mean arterial pressure, being parous and previous PE, with areas under the receiver-operating characteristics curves of 0.86 (95% CI, 0.77-0.95), 0.91 (95% CI, 0.85-0.97) and 0.93 (95% CI, 0.86-0.99) at 20, 24 and 28 weeks, respectively, and was superior to models using the sFlt-1/PlGF ratio alone or uterine artery mean pulsatility index.ConclusionsThe sFlt-1/PlGF ratio can improve prediction of early-onset PE for women at risk of this condition. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

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Differential activation of placental unfolded protein response pathways implies heterogeneity in causation of early- and late-onset pre-eclampsia.

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Differential activation of placental unfolded protein response pathways implies heterogeneity in causation of early- and late-onset pre-eclampsia.

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