Centre of Molecular Inflammation Research (CEMIR), Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology (NTNU), 7491 Trondheim, Norway.
Women's Health and Perinatology Research Group, Department of Clinical Medicine, UiT-The Arctic University of Norway, 9037 Tromsø, Norway.
Int J Mol Sci. 2022 Feb 10;23(4):1966. doi: 10.3390/ijms23041966.
Utero-placental development in pregnancy depends on direct maternal-fetal interaction in the uterine wall decidua. Abnormal uterine vascular remodeling preceding placental oxidative stress and placental dysfunction are associated with preeclampsia and fetal growth restriction (FGR). Oxidative stress is counteracted by antioxidants and oxidative repair mechanisms regulated by the transcription factor nuclear factor erythroid 2-related factor 2 (NRF2). We aimed to determine the decidual regulation of the oxidative-stress response by NRF2 and its negative regulator Kelch-like ECH-associated protein 1 (KEAP1) in normal pregnancies and preeclamptic pregnancies with and without FGR. Decidual tissue from 145 pregnancies at delivery was assessed for oxidative stress, non-enzymatic antioxidant capacity, cellular NRF2- and KEAP1-protein expression, and NRF2-regulated transcriptional activation. Preeclampsia combined with FGR was associated with an increased oxidative-stress level and NRF2-regulated gene expression in the decidua, while decidual NRF2- and KEAP1-protein expression was unaffected. Although preeclampsia with normal fetal growth also showed increased decidual oxidative stress, NRF2-regulated gene expression was reduced, and KEAP1-protein expression was increased in areas of high trophoblast density. The trophoblast-dependent KEAP1-protein expression in preeclampsia with normal fetal growth indicates control of decidual oxidative stress by maternal-fetal interaction and underscores the importance of discriminating between preeclampsia with and without FGR.
胎盘在妊娠期间的发育依赖于子宫壁蜕膜中的直接母婴相互作用。胎盘氧化应激和胎盘功能障碍之前的异常子宫血管重塑与子痫前期和胎儿生长受限（FGR）有关。抗氧化剂和转录因子核因子红细胞 2 相关因子 2（NRF2）调节的氧化修复机制可抵抗氧化应激。我们旨在确定 NRF2 及其负调节剂 Kelch 样 ECH 相关蛋白 1（KEAP1）在正常妊娠和子痫前期妊娠及其有无 FGR 中对蜕膜氧化应激反应的调节。对 145 例分娩时的蜕膜组织进行了氧化应激、非酶抗氧化能力、细胞 NRF2 和 KEAP1 蛋白表达以及 NRF2 调节的转录激活评估。子痫前期合并 FGR 与蜕膜中氧化应激水平和 NRF2 调节的基因表达增加有关，而蜕膜 NRF2 和 KEAP1 蛋白表达不受影响。尽管正常胎儿生长的子痫前期也显示出蜕膜氧化应激增加，但 NRF2 调节的基因表达减少，KEAP1 蛋白表达在高滋养细胞密度区域增加。正常胎儿生长的子痫前期中依赖于滋养细胞的 KEAP1 蛋白表达表明，蜕膜氧化应激受到母婴相互作用的控制，并强调了区分有无 FGR 的子痫前期的重要性。
