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. © 2014 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Serum HtrA1 is differentially regulated between early-onset and late-onset preeclampsia

“…However, HtrAs are known to function in protecting cells from stress by degrading unfolded, misfolded or otherwise aberrant proteins, and they may also serve as chaperones to protect protein structure [13,42]. Recently, a study investigating stress-signalling pathways including unfolded protein response, heat-shock proteins and MAPK stress pathways, suggests that placental stress may contribute to the pathophysiology of earlyonset PE, but not late-onset PE [43]. It is thus possible that an increase in serum HtrA1 may reflect placental stress in early-onset PE.…”

Interleukin-10: A Pleiotropic Regulator in Pregnancy

“…121–127 Burton and coworkers recently reported that increased expression levels of many components in the UPR such as phosphorylated IRE1a, ATF6, XBP1 and BiP were observed only in the placenta from the early-onset PE, but not from both the late-onset PE and normotensive controls, suggesting a higher level of the ER stress and UPR activation in the placenta from early-onset PE. 126 …”

Activation of Villous Trophoblastic p38 and ERK1/2 Signaling Pathways in Preterm Preeclampsia and HELLP Syndrome

“…Studies focusing on placental injury or the placental dysregulation of genes in preeclampsia have revealed a complex interplay between hypoxia and ischemia in the activation or inhibition of various signaling pathways, leading to altered gene expression and placental functions [11–17, 30]. Our recent microarray study [7] has shown the differential placental expression of a set of genes in preterm preeclampsia and HELLP syndrome, which are induced by villous trophoblast differentiation [7, 31, 32].…”