title: 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 AMPKα 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-IRE1α, 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-eIF2α, ATF6, P-IRE1α, GRP78 and GRP94, in BeWo cells. By contrast, the pro-inflammatory cytokines TNFα and IL-1β induced only mild activation of P-eIF2α 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.
authors.affiliation: Centre for Trophoblast Research, University of Cambridge, UK.
authors.forename: Hong Wa
authors.initials: HW
authors.lastname: Yung
authors.forename: Daniel
authors.initials: D
authors.lastname: Atkinson
authors.forename: Tim
authors.initials: T
authors.lastname: Campion-Smith
authors.forename: Matts
authors.initials: M
authors.lastname: Olovsson
authors.forename: D Stephen
authors.initials: DS
authors.lastname: Charnock-Jones
authors.forename: Graham J
authors.initials: GJ
authors.lastname: Burton
mesh_terms: D000328:Adult; D002478:Cells, Cultured; D000091342:Endoplasmic Reticulum Chaperone BiP; D005260:Female; D005317:Fetal Growth Retardation / Q000378:metabolism; D005865:Gestational Age; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D010920:Placenta / Q000378:metabolism* / Q000473:pathology; D011225:Pre-Eclampsia / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D011247:Pregnancy; D015398:Signal Transduction / Q000502:physiology; D056811:Unfolded Protein Response / Q000502:physiology*
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; D018840:HSP70 Heat-Shock Proteins; C000717247:HSPA5 protein, human; D008565:Membrane Proteins; C018551:glucose-regulated proteins
keywords: cell stress responses; growth restriction; placenta; pre-eclampsia; pregnancy; unfolded protein response