Divergent Regulation of Decidual Oxidative-Stress Response by NRF2 and KEAP1 in Preeclampsia with and without Fetal Growth Restriction.

Siv Boon Mundal,Purusotam Basnet,Ganesh Acharya,Gabriela Brettas Silva,Mattijs Elschot,Johanne Johnsen Rakner,Line Bjørge,Marie Austdal,Eric Keith Moses,Jenny Ostrop,Liv Cecilie Vestrheim Thomsen,Lobke Marijn Gierman,Siril Skaret Bakke,Ann-Charlotte Iversen

doi:10.3390/ijms23041966

Abstract

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.

Highlights

Preeclampsia is an inflammatory multisystem syndrome affecting 2–5% of pregnancies, and it is often further complicated by fetal growth restriction (FGR) [1–3]
Had lower birth weight and placental weight, placental weight ratio, and gestational age at delivery compared to preeclamptic pregnancies without FGR
This study shows the protein expression of the oxidative-stress regulator nuclear factor erythroid 2-related factor 2 (NRF2) and its

Summary

Introduction

Preeclampsia is an inflammatory multisystem syndrome affecting 2–5% of pregnancies, and it is often further complicated by fetal growth restriction (FGR) [1–3]. Both disorders originate from placental dysfunction due to inadequate blood supply via decidual spiral arteries to the placenta. The decidua basalis develops from the endometrium at the blastocyst implantation site and is composed of spiral arteries, decidualized endometrial cells, maternal immune cells, fetal extravillous trophoblasts, fibrinoid layers and endometrial glands [4]. Close interactions between fetal extravillous trophoblasts and maternal cells are crucial for optimal remodeling of the decidual spiral arteries during pregnancy. Impaired spiral-artery remodeling causes malperfusion of the placenta and leads to placental oxidative-, endoplasmic reticulum (ER)- and inflammatory-stress culminating in established placental dysfunction. The dysfunctional placenta releases stress signals and anti-angiogenic factors to the maternal circulation, leading to endothelial dysfunction and, eventually, to the clinical signs of preeclampsia [1,2]

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