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Cited by 156Pregnancy and preeclampsia studiesEndoplasmic Reticulum Stress and DiseaseNeurological Complications and Syndromes

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

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Yung, Hong Wa, Atkinson, Daniel, Campion‐Smith, Tim, Olovsson, Matts, Charnock‐Jones, D Stephen, Burton, Graham J·2014·The Journal of Pathology
DOI 10.1002/path.4394PMC PMC4277692
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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 α 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 α, 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% O 2) induced equivalent activation of UPR pathways, including P‐eIF2 α, ATF6, P‐IRE1 α, GRP78 and GRP94, in BeWo cells. By contrast, the pro‐inflammatory cytokines TNF α and IL‐1 β induced only mild activation of P‐eIF2 α 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. © 2014 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

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  • UPR signaling cascades are activated in placentas from cases of growth restriction and early-onset pre-eclampsia, but no data are yet available for pregnancies complicated by maternal obesity or other metabolic disorders.

    “These cascades are activated in placentas from cases of growth restriction and early-onset pre-eclampsia (595, 596), but no data are yet available for pregnancies complicated by maternal obesity or other metabolic disorders.”

    From Placental Origins of Chronic Disease (2016) · cites this paper as [595]

  • More severe UPR activation is seen in human placentas from growth-restricted pregnancies, particularly early-onset pre-eclampsia.

    “More severe activation is seen in human placentas from growth-restricted pregnancies (596), and particularly in cases of early-onset pre-eclampsia (595).”

    From Placental Origins of Chronic Disease (2016) · cites this paper as [595]

  • Activation of the UPR has been reported in placentas from cases of early-onset, but not late-onset, preeclampsia, when there is often accompanying growth restriction.

    “Activation of the UPR has also been reported in placentas from cases of early-onset, but not late-onset, preeclampsia (595), when there is often accompanying growth restriction.”

    From Placental Origins of Chronic Disease (2016) · cites this paper as [595]

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Authors
Yung, H. W., Atkinson, D., Campion‐Smith, T., Olovsson, M., Charnock‐Jones, D. S., & Burton, G. J.
Affiliations
  • University of Cambridge (GB)
  • Uppsala University (SE)
  • Centre for Trophoblast Research University of Cambridge UK
Corresponding author
Burton, Graham J
ORCID
Venue
The Journal of Pathology
Publisher
Wiley
Published
2014-08-06
Volume
234
Issue
2
Pages
262-276
ISSN
  • 0022-3417 (ISSN-L)
  • 1096-9896
DOI
10.1002/path.4394
PMC
PMC4277692
OpenAlex
W1519784590
Cited by
156
References
41
Citations by year
2026: 10 · 2025: 9 · 2024: 9 · 2023: 7 · 2022: 18 · 2021: 19 · 2020: 20 · 2019: 14 · 2018: 13 · 2017: 10 · 2016: 11 · 2015: 12 · 2014: 3 · 2013: 1
FWCI
12.74
Type
journal article
Language
en
Open access
Licence
Locations
  • The Journal of Pathology (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • KTH Publication Database DiVA (KTH Royal Institute of Technology) (submittedVersion, other-oa)
Funders
Wellcome Trust (084804/2/08/Z)
Topics
  • Health Sciences › Medicine › Obstetrics and Gynecology › Pregnancy and preeclampsia studies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
  • Health Sciences › Medicine › Psychiatry and Mental health › Neurological Complications and Syndromes
Keywords
preeclampsia, early-onset preeclampsia, late-onset preeclampsia, hypoxia/reoxygenation, MAPK signaling, heat shock proteins, AMPKα, Akt signaling, IRE1α, ATF6, XBP1, GRP78, GRP94, eIF2α, TNF-α, IL-1β, chorioamnionitis, BeWo cells, placental pathology
MeSH terms
Endoplasmic Reticulum Chaperone BiP, Adult, Cells, Cultured, Female, Fetal Growth Retardation, Gestational Age, Humans, Membrane Proteins, Placenta, Pre-Eclampsia, Pregnancy, Signal Transduction, HSP70 Heat-Shock Proteins, Unfolded Protein Response

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