Senescent Changes and Endoplasmic Reticulum Stress May Be Involved in the Pathogenesis of Missed Miscarriage.

Yunhui Tang,Jing Gao,Haiyan Liu,Xinyan Zhang,Hua Feng,Qi Chen,Yi Zhang,Fang Guo

doi:10.3389/fcell.2021.656549

Abstract

BackgroundSenescence is involved in many complications of pregnancy. However, whether senescent changes are also associated with missed miscarriage has not been fully investigated.MethodsThe levels of p16, p21, and γH2AX, markers of senescence, were measured in placentas collected from women with missed miscarriage by immunohistochemistry and Western blotting. Levels of misfolded proteins in missed miscarriage placentas or normal first-trimester placenta that had been treated with H2O2 (100 μM) or extracellular vesicles (EVs) collected from missed miscarriage placental explant culture were measured by fluorescent compound, thioflavin-T. The production of reactive oxygen species (ROS) by missed miscarriage placentas was measured by CellROX® Deep Red.ResultsIncreased levels of p16, p21, and γH2AX were presented in missed miscarriage placentas compared to controls. Increased levels of misfolded proteins were shown in missed miscarriage placentas, but not in EVs that were collected from missed miscarriage placentas. The ROS production was significantly increased in missed miscarriage placental explant cultures. Increased levels of misfolded proteins were seen in the normal first-trimester placenta that had been treated with H2O2 compared to untreated.ConclusionOur data demonstrate that there are increases in senescence and endoplasmic reticulum stress and ROS production in missed miscarriage placenta. Oxidative stress and an accumulation of misfolded proteins in missed miscarriage placentas may contribute to the changes of senescence and endoplasmic reticulum stress seen in missed miscarriage placentas.

Highlights

A missed/silent miscarriage is one type of miscarriage in which the fetus did not form or has died, but the placenta and embryonic tissues still exist
To investigate whether there is a change in senescent markers in placentas from missed miscarriage, we examined the expression of p16 and p21, which are markers of senescence
Compared to control placentas (Figures 1A,B, 2A,B), a representative image showed that the expression of p16 (Figures 1C,D), or p21 (Figures 2C,D) was predominantly increased in syncytiotrophoblasts in placentas from missed miscarriage

Summary

Introduction

A missed/silent miscarriage is one type of miscarriage in which the fetus did not form or has died, but the placenta and embryonic tissues still exist. A number of studies suggested that defective placentation, including morphological and functional changes in trophoblasts, is associated with many complicated pregnancies, including miscarriage (Hustin et al, 1990; Jauniaux et al, 2003; Jauniaux and Burton, 2005). A growth of evidence suggested that increased placental oxidative stress represents a common pathogenesis of miscarriage, which may result in impaired trophoblast invasion. These studies indicated that oxidative stress in syncytiotrophoblasts is extensive and is likely a major contributory factor to miscarriage (Hustin et al, 1990; Hempstock et al, 2003; Burton and Jauniaux, 2004). Whether senescent changes are associated with missed miscarriage has not been fully investigated

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