Department of Cancer Research and Molecular Medicine, Faculty of Medicine, Norwegian, University of Science and Technology (NTNU), Women and Children's Centre, N-7006 Trondheim, Norway.
Placenta. 2011 Nov;32(11):823-9. doi: 10.1016/j.placenta.2011.08.005. Epub 2011 Sep 9.
Endoplasmic reticulum (ER) stress has been implicated in both pre-eclampsia (PE) and fetal growth restriction (FGR), and is characterised by activation of three signalling branches: 1) PERK-pEIF2α, 2) ATF6 and 3) splicing of XBP1(U) into XBP1(S). To evaluate the contribution of ER stress in the pathogenesis of PE relative to FGR, we compared levels of ER stress markers in decidual tissue from pregnancies complicated by PE and/or FGR.
Whole-genome transcriptional profiling was performed on decidual tissue from women with PE (n = 13), FGR (n = 9), PE+FGR (n = 24) and controls (n = 58), and used for pathway and targeted transcriptional analyses of ER stress markers. The expression and cellular localisation of ER stress markers was assesses by Western blot and immunofluorescence analyses.
Increased ER stress was observed in FGR and PE+FGR, including both the PERK-pEIF2α and ATF6 signalling branches, whereas ER stress was less evident in isolated PE. However, these cases demonstrated elevated levels of XBP1(U) protein. ATF6 and XBP1 immunoreactivity was detected in most (>80%) extravillous trophoblasts, decidual cells and macrophages. No difference in the proportion of immunopositive cells or staining pattern was observed between study groups.
Increased PERK-pEIF2α and ATF6 signalling have been associated with decreased cellular proliferation and may contribute to the impaired placental growth characterising pregnancies with FGR and PE+FGR. XBP1(U) has been proposed as a negative regulator of ER stress, and increased levels in PE may reflect a protective mechanism against the detrimental effects of ER stress.
内质网（ER）应激与子痫前期（PE）和胎儿生长受限（FGR）均有关联，其特征在于三个信号通路的激活：1）PERK-pEIF2α，2）ATF6 和 3）XBP1（U）剪接为 XBP1（S）。为了评估 ER 应激在 PE 发病机制中的作用相对于 FGR，我们比较了合并 PE 和/或 FGR 的妊娠蜕膜组织中 ER 应激标志物的水平。
对患有 PE（n=13）、FGR（n=9）、PE+FGR（n=24）和对照组（n=58）的女性蜕膜组织进行全基因组转录谱分析，并用于 ER 应激标志物的通路和靶向转录分析。通过 Western blot 和免疫荧光分析评估 ER 应激标志物的表达和细胞定位。
在 FGR 和 PE+FGR 中观察到 ER 应激增加，包括 PERK-pEIF2α 和 ATF6 信号通路，而孤立性 PE 中 ER 应激则不太明显。然而，这些病例显示 XBP1（U）蛋白水平升高。ATF6 和 XBP1 免疫反应性在大多数（>80%）绒毛外滋养细胞、蜕膜细胞和巨噬细胞中均有检测到。在研究组之间未观察到免疫阳性细胞的比例或染色模式有差异。
PERK-pEIF2α 和 ATF6 信号的增加与细胞增殖减少有关，可能导致 FGR 和 PE+FGR 中胎盘生长受损。XBP1（U）已被提出作为 ER 应激的负调节剂，PE 中水平升高可能反映了一种针对 ER 应激有害影响的保护机制。
