The Placental Transcriptome in Late Gestational Hypoxia Resulting in Murine Intrauterine Growth Restriction Parallels Increased Risk of Adult Cardiometabolic Disease

Alison Chu,Shanthie Thamotharan,Madhuri Wadehra,Amy Cosi,David Casero,Sherin U Devaskar

doi:10.1038/s41598-018-37627-y

Abstract

Intrauterine growth restriction (IUGR) enhances risk for adult onset cardiovascular disease (CVD). The mechanisms underlying IUGR are poorly understood, though inadequate blood flow and oxygen/nutrient provision are considered common endpoints. Based on evidence in humans linking IUGR to adult CVD, we hypothesized that in murine pregnancy, maternal late gestational hypoxia (LG-H) exposure resulting in IUGR would result in (1) placental transcriptome changes linked to risk for later CVD, and 2) adult phenotypes of CVD in the IUGR offspring. After subjecting pregnant mice to hypoxia (10.5% oxygen) from gestational day (GD) 14.5 to 18.5, we undertook RNA sequencing from GD19 placentas. Functional analysis suggested multiple changes in structural and functional genes important for placental health and function, with maximal dysregulation involving vascular and nutrient transport pathways. Concordantly, a ~10% decrease in birthweights and ~30% decrease in litter size was observed, supportive of placental insufficiency. We also found that the LG-H IUGR offspring exhibit increased risk for CVD at 4 months of age, manifesting as hypertension, increased abdominal fat, elevated leptin and total cholesterol concentrations. In summary, this animal model of IUGR links the placental transcriptional response to the stressor of gestational hypoxia to increased risk of developing cardiometabolic disease.

Highlights

Placental blood flow is a key regulator of nutrient and oxygen provision to the growing fetus
Our animal study demonstrates that late gestational hypoxia exposure mimics placental insufficiency resulting in decreased birth weight and litter sizes, and an increased risk of cardiovascular disease in adulthood for the hypoxia-exposed offspring
Though poor nutrient provision and blood flow to the fetus are certainly implicated as important components of the IUGR condition, we chose to parse out and focus on chronic maternal hypoxia exposure as it mimics the common end point of poor oxygen delivery to the fetus thought to incur adverse fetal effects as seen in idiopathic human placental insufficiency/IUGR

Summary

Introduction

Placental blood flow is a key regulator of nutrient and oxygen provision to the growing fetus. Preferentially affects nutrient transfer culminating in a chronic reduction in uteroplacental blood flow[10], the uterine artery ligation model results in abrupt reduction in placental blood flow during late pregnancy. Murine models of placental insufficiency secondary to gestational hypoxia exposure have been reported to affect fetal cardiovascular development and programming of adult cardiometabolic disease by affecting inflammation and fat deposition[11], as well as endothelial function and hemodynamics[12]. Recent murine studies have linked gestational hypoxia to programming of adult cardiometabolic disease[11,12], with phenotypes of adiposity, altered cholesterol levels, insulin resistance, inflammation, and endothelial dysfunction, as well as renal disease[20,21]. These adult outcomes have not been linked to the placental transcriptome. Our specific research objectives were to evaluate: (1) the effects of gestational hypoxia on the pre-parturient placental transcriptome as related to vascular function, metabolic pathways, and inflammation, and (2) phenotypes of cardiometabolic disease in hypoxia-exposed offspring, thereby providing a foundation for molecular mechanisms by which intra-uterine stressors can be linked to adult cardiometabolic disease

Methods

Results

Conclusion