{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T00:36:01Z","timestamp":1791246961686,"version":"4.1.0"},"reference-count":41,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2014,8,6]],"date-time":"2014-08-06T00:00:00Z","timestamp":1407283200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/3.0\/"}],"funder":[{"DOI":"10.13039\/100004440","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["084804\/2\/08\/Z"],"award-info":[{"award-number":["084804\/2\/08\/Z"]}],"id":[{"id":"10.13039\/100004440","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["pathsocjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Pathology"],"published-print":{"date-parts":[[2014,10]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Based on gestational age at diagnosis and\/or delivery, pre\u2010eclampsia (PE) is commonly divided into early\u2010onset (&lt;34 weeks) and late\u2010onset (\u226534 weeks) forms. Recently, the distinction between \u2018placental\u2019 and \u2018maternal\u2019 causation has been proposed, with \u2018placental\u2019 cases being more frequently associated with early\u2010onset and intrauterine growth restriction. To test whether molecular placental pathology varies according to clinical presentation, we investigated stress\u2010signalling pathways, including unfolded protein response (UPR) pathways, MAPK stress pathways, heat\u2010shock proteins and AMPK<jats:italic>\u03b1<\/jats:italic> in placentae delivered by caesarean section for clinical indications at different gestational ages. Controls included second\u2010trimester, pre\u2010term and normal\u2010term placentae. BeWo cells were used to investigate how these pathways react to different severities of hypoxia\u2013reoxygenation (H\/R) and pro\u2010inflammatory cytokines. Activation of placental UPR and stress\u2010response pathways, including P\u2010IRE1<jats:italic>\u03b1<\/jats:italic>, ATF6, XBP\u20101, GRP78 and GRP94, P\u2010p38\/p38 and HSP70, was higher in early\u2010onset PE than in both late\u2010onset PE and normotensive controls (NTCs), with a clear inflection around 34 weeks. Placentae from \u2265 34 weeks PE and NTC were indistinguishable. Levels of UPR signalling were similar between second\u2010trimester and term controls, but were significantly higher in pre\u2010term \u2018controls\u2019 delivered vaginally for chorioamnionitis and other conditions. Severe H\/R (1\/20% O<jats:sub>2<\/jats:sub>) induced equivalent activation of UPR pathways, including P\u2010eIF2<jats:italic>\u03b1<\/jats:italic>, ATF6, P\u2010IRE1<jats:italic>\u03b1<\/jats:italic>, GRP78 and GRP94, in BeWo cells. By contrast, the pro\u2010inflammatory cytokines TNF<jats:italic>\u03b1<\/jats:italic> and IL\u20101<jats:italic>\u03b2<\/jats:italic> induced only mild activation of P\u2010eIF2<jats:italic>\u03b1<\/jats:italic> and GRP78. AKT, a central regulator of cell proliferation, was reduced in the &lt; 34 weeks PE placentae and severe H\/R\u2010treated cells, but not in other conditions. These findings provide the first molecular evidence that placental stress may contribute to the pathophysiology of early\u2010onset pre\u2010eclampsia, whereas that is unlikely to be the case in the late\u2010onset form of the syndrome. \u00a9 2014 The Authors. <jats:italic>The Journal of Pathology<\/jats:italic> published by John Wiley &amp; Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.<\/jats:p>","DOI":"10.1002\/path.4394","type":"journal-article","created":{"date-parts":[[2014,6,16]],"date-time":"2014-06-16T14:54:02Z","timestamp":1402930442000},"page":"262-276","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":146,"title":["Differential activation of placental unfolded protein response pathways implies heterogeneity in causation of early\u2010 and late\u2010onset pre\u2010eclampsia"],"prefix":"10.1002","volume":"234","author":[{"given":"Hong Wa","family":"Yung","sequence":"first","affiliation":[{"name":"Centre for Trophoblast Research University of Cambridge  UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Atkinson","sequence":"additional","affiliation":[{"name":"Centre for Trophoblast Research University of Cambridge  UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tim","family":"Campion\u2010Smith","sequence":"additional","affiliation":[{"name":"Department of Women's and Children's Health Uppsala University  Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matts","family":"Olovsson","sequence":"additional","affiliation":[{"name":"Department of Women's and Children's Health Uppsala University  Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D Stephen","family":"Charnock\u2010Jones","sequence":"additional","affiliation":[{"name":"Centre for Trophoblast Research University of Cambridge  UK"},{"name":"Department of 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