NR4A2 expression is not altered in placentas from cases of growth restriction or preeclampsia, but is reduced in hypoxic cytotrophoblast

Natasha De Alwis,Owen Stock,Natasha Pritchard,Stefan C Kane,Natalie J Hannan,Amanda Henry,Sally Beard,Tu’Uhevaha J Kaitu’U-Lino,Sean Seeho,Joanne M Said,Katie M Groom,Scott Petersen,Natalie K Binder,Susan P Walker,Stephen Tong

doi:10.1038/s41598-021-00192-y

Abstract

Nuclear Receptor Subfamily 4 Group A Member 2 (NR4A2) transcripts are elevated in the circulation of individuals whose pregnancies are complicated by preterm fetal growth restriction (FGR). In this paper, we show that the cases with preeclampsia (PE) have increased circulating NR4A2 transcripts compared to those with normotensive FGR. We aimed to establish whether the dysfunctional placenta mirrors the increase in NR4A2 transcripts and further, to uncover the function of placental NR4A2. NR4A2 expression was detected in preterm and term placental tissue; expressed higher at term. NR4A2 mRNA expression and protein were not altered in placentas from preterm FGR or PE pregnancies. Hypoxia (1% O2 compared to 8% O2) significantly reduced cytotrophoblast NR4A2 mRNA expression, but not placental explant NR4A2 expression. Silencing cytotrophoblast NR4A2 expression under hypoxia (via short interfering (si)RNAs) did not alter angiogenic Placental Growth Factor, nor anti-angiogenic sFlt-1 mRNA expression or protein secretion, but increased expression of cellular antioxidant, oxidative stress, inflammatory, and growth genes. NR4A2 expression was also not altered in a model of tumour necrosis factor-α-induced endothelial dysfunction, or with pravastatin treatment. Further studies are required to identify the origin of the circulating transcripts in pathological pregnancies, and investigate the function of placental NR4A2.

Highlights

Nuclear Receptor Subfamily 4 Group A Member 2 (NR4A2) transcripts are elevated in the circulation of individuals whose pregnancies are complicated by preterm fetal growth restriction (FGR)
We previously reported increased NR4A2 transcripts in the circulation of women whose pregnancies were complicated by preterm fetal growth restriction (< 34 weeks gestation)[13]
NR4A2 expression was higher in term placental tissue compared to preterm placental tissue (Fig. 2)

Summary

Introduction

Nuclear Receptor Subfamily 4 Group A Member 2 (NR4A2) transcripts are elevated in the circulation of individuals whose pregnancies are complicated by preterm fetal growth restriction (FGR). NR4A2 mRNA expression and protein were not altered in placentas from preterm FGR or PE pregnancies. Placental dysfunction is associated with impaired maternal uterine spiral artery remodelling, resulting in a high resistance, pulsatile blood supply This compromised blood supply restricts nutrient and oxygen delivery to the fetus and causes oxidative stress, fluctuating oxygen tensions, and ischemia[7,8], thereby impacting fetal growth. In the Fetal OXygenation (FOX) Study, we identified altered mRNA transcript levels in the circulation of women whose pregnancies were complicated by preterm fetal growth restriction, associated with placental insufficiency[13]. NR4A2 is a transcription factor and early response gene, and has been implicated in many pathways and diseases including inflammation and cell p roliferation[14,15,16,17,18,19,20,21], intestinal regeneration after ischemic/reperfusion injury[22,23], liver fibrosis24, cancer[19,25,26,27], impaired neurodevelopment and a utism[28,29,30], Parkinson’s d isease[31,32,33], and cardiovascular disease[34,35,36]

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