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Cited by 112High Altitude and HypoxiaPregnancy and preeclampsia studiesEndoplasmic Reticulum Stress and Disease

Evidence of endoplasmic reticulum stress and protein synthesis inhibition in the placenta of non‐native women at high altitude

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Yung, Hong Wa, Cox, Mathew, van Patot, Martha Tissot, Burton, Graham J.·2012·The FASEB Journal
DOI 10.1096/fj.11-190082PMC PMC3336782
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Abstract

Pregnancy at high altitude is associated with a reduction in birth weight of ~100 g/1000 m of ascent. The underlying mechanisms are unclear but may involve alteration in energy‐demanding activities, such as protein synthesis. To test this hypothesis, both in vivo and in vitro approaches were used. Placental tissues from pregnant women residing at 3100 m were studied, and placental cells were incubated under hypoxia. In the 3100‐m placentas, we observed dilation of endoplasmic reticulum (ER) cisternae, increased phosphorylation of eukaryotic initiation factor 2 subunit α (P‐eIF2α), reduced AKT phosphorylation, and reduced P‐4E‐BP1 but increased 4E‐BP1 protein compared to sea level controls. These findings suggest the presence of ER stress and protein synthesis inhibition. Hypoxia (1% O 2 ) reduced proliferation of trophoblast‐like JEG‐3 cells, BeWo cells, and placental fibroblasts by ~40, ~60, and ~18%, respectively. Sublethal dosage of salubrinal, an eIF2α phosphatase inhibitor, increased P‐eIF2α and reduced BeWo cell and placental fibroblast proliferation by ~50%. Administration of the PI‐3K inhibitor LY294002 also reduced JEG‐3 proliferation. Our results demonstrate that exposure to chronic hypobaric hypoxia causes mild placental ER stress, which, in turn, modulates protein synthesis and slows proliferation. These effects may account for the reduced placental villous volume, and contribute to the low birth weight that typifies high‐altitude populations.—Yung, H. W., Cox, M., Tissot van Patot, M., Burton, G. J. Evidence of endoplasmic reticulum stress and protein synthesis inhibition in the placenta of non‐native women at high altitude. FASEB J. 26, 1970‐1981 (2012). www.fasebj.org

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  • Mild activation of the UPR, with phosphorylation of eIF2α alone, is reported in the high-altitude human placenta, where it may mediate homeostatic adaptations to hypobaric hypoxia.

    “Mild activation of the UPR, with phosphorylation of eIF2α alone, has been reported in the high-altitude human placenta, where it may mediate homeostatic adaptations to the hypobaric hypoxia experienced (598).”

    From Placental Origins of Chronic Disease (2016) · cites this paper as [598]

  • Evidence of translational arrest has been reported in human placentas from normal healthy pregnancies at high altitude (3,100 m) where growth of the villus tree is impaired.

    “Equally, evidence of translational arrest has been reported in human placentas from normal healthy pregnancies at high altitude (3,100 m) where growth of the villus tree is impaired (598).”

    From Placental Origins of Chronic Disease (2016) · cites this paper as [598]

  • These changes can be recapitulated by exposing trophoblast cell lines to hypoxia (1% O2), when they are associated with reduced cell proliferation.

    “These changes can be recapitulated by exposing trophoblast cell lines to hypoxia (1% O2), when they are associated with reduced cell proliferation.”

    From Placental Origins of Chronic Disease (2016) · cites this paper as [598]

  • These high-altitude placentas displayed increased phosphorylation of eIF2α, reduced phosphorylation of AKT and 4E-BP1, and an increase in total 4E-BP1 that will favor sequestration of eIF4E.

    “These placentas displayed increased phosphorylation of eIF2α, reduced phosphorylation of AKT and 4E-BP1, and an increase in total 4E-BP1 that will favor sequestration of eIF4E.”

    From Placental Origins of Chronic Disease (2016) · cites this paper as [598]

  • There is evidence for a decrease in protein synthesis in the placenta of non-native women at high altitude.

    “However, there is evidence for a decrease in protein synthesis in the placenta of non-native women at high altitude (598).”

    From Placental Origins of Chronic Disease (2016) · cites this paper as [598]

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Authors
Yung, H. W., Cox, M., van Patot, M. T., & Burton, G. J.
Affiliations
  • University of Cambridge (GB)
  • Centre for Trophoblast Research University of Cambridge Cambridge UK
Corresponding author
Burton, Graham J.
ORCID
Venue
The FASEB Journal
Publisher
Wiley
Published
2012-01-20
Volume
26
Issue
5
Pages
1970-1981
ISSN
  • 0892-6638 (ISSN-L)
  • 1530-6860
DOI
10.1096/fj.11-190082
PMC
PMC3336782
OpenAlex
W2115115666
Cited by
112
References
62
Citations by year
2026: 2 · 2025: 9 · 2024: 5 · 2023: 6 · 2022: 8 · 2021: 9 · 2020: 8 · 2019: 10 · 2018: 9 · 2017: 7 · 2016: 8 · 2015: 12 · 2014: 5 · 2013: 10 · 2012: 4
FWCI
5.97
Type
journal article
Language
en
Open access
Licence
Locations
  • The FASEB Journal (publishedVersion, cc-by-nc)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
Funders
Wellcome Trust (084804/2/08/Z)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › High Altitude and Hypoxia
  • Health Sciences › Medicine › Obstetrics and Gynecology › Pregnancy and preeclampsia studies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
Keywords
endoplasmic reticulum stress, hypoxia, high altitude, placenta, protein synthesis inhibition, eIF2α phosphorylation, 4E-BP1, Akt phosphorylation, PI3K signaling, salubrinal, cell proliferation, low birth weight, trophoblast
MeSH terms
Altitude, Endoplasmic Reticulum, Female, Humans, Phosphoproteins, Phosphorylation, Placenta, Pregnancy, Protein Biosynthesis, Blotting, Western, Eukaryotic Initiation Factor-2, Oxidative Stress, Cell Cycle Proteins, Cell Line, Tumor, Adaptor Proteins, Signal Transducing, Proto-Oncogene Proteins c-akt, Real-Time Polymerase Chain Reaction

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