# Deciphering Roles of Placental Endoplasmic Reticulum Stress in Complicated Pregnancies and Beyond: The Power of Mouse Models

## TL;DR

Mouse models show that placental ER stress disrupts hormone signaling, leading to pregnancy complications and long-term maternal health risks.

## Contribution

First demonstration of ER stress in placentas from complicated pregnancies and its role in maternal maladaptation.

## Key findings

- ER stress in the placenta disrupts PI-3K-AKT signaling and angiogenic factors, causing fetal growth restriction and pre-eclampsia.
- Placental ER stress leads to maternal maladaptation by impairing placental endocrine signaling.
- Placental dysfunction from ER stress has long-term effects on maternal cardio-metabolic health.

## Abstract

What are the main findings?
Transgenic mouse models confirm that placental ER stress-mediated loss of PI-3K-AKT signalling and bioactivity of angiogenic factors play key pathophysiological roles in fetal growth restriction and early-onset pre-eclampsia.A placental endocrine-specific transgenic model suggests that ER stress-mediated loss of placental signals results in maternal maladaptation to pregnancy.

Transgenic mouse models confirm that placental ER stress-mediated loss of PI-3K-AKT signalling and bioactivity of angiogenic factors play key pathophysiological roles in fetal growth restriction and early-onset pre-eclampsia.

A placental endocrine-specific transgenic model suggests that ER stress-mediated loss of placental signals results in maternal maladaptation to pregnancy.

What are the implications of the main findings?
Targeting placental ER stress may provide a potential therapeutic intervention reducing complications of human pregnancy.Placental dysfunction has longer-term implications for maternal health than the duration of the index pregnancy.

Targeting placental ER stress may provide a potential therapeutic intervention reducing complications of human pregnancy.

Placental dysfunction has longer-term implications for maternal health than the duration of the index pregnancy.

Over a quarter of human pregnancies are associated with complications, including fetal growth restriction, pre-eclampsia and gestational diabetes. These are major causes of maternal and fetal morbidity and mortality, and also lead to a 3–5-fold increased risk of subsequent development of cardio-metabolic diseases. Although the mechanistic details remain elusive, a dysfunctional placenta is central to the pathophysiology of these conditions. The placenta ensures sufficient nutrient supply to the fetus without compromising maternal wellbeing. This balance is achieved by the secretion of large quantities of placental-derived peptide hormones into the maternal circulation. Consequently, the placenta is susceptible to endoplasmic reticulum (ER) stress, and we were the first to demonstrate the presence of ER stress in placentas from complicated pregnancies. The mouse placenta provides an ideal model for studying the impact of ER stress as it is composed of two distinct regions, an endocrine zone and a transport zone. Therefore, perturbation of placental endocrine function by ER stress can be generated without directly affecting its capacity for nutrient exchange. In this review, we summarise the current literature on how transgenic mouse models enhance our understanding of ER stress-mediated perturbation of placental endocrine function, and its contribution to the pathophysiology of pregnancy complications and life-long health.