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Maternal Hypoxemia and Oxidative Stress

ABSTRACT: This project seeks to understand the metabolic consequences of gestational hypoxia on fetal, newborn, and adult plasma, arteries and other tissues using a sheep model of fetal growth restriction. Specifically we are interested testing the hypothesis that gestational hypoxia will result in discernable differences in glucose and lipid metabolism in tissues and plasma as well influence indicators of oxidative stress and inflammation. These studies aim to delineate pathways and biomarkers that help explain how hypoxia leads to the development of neonatal as well as adult-onset diseases associated with chronic hypoxia that are inter-related with fetal growth restriction. From a vascular perspective this includes cerebrovascular hemorrhage and pulmonary hypertension in the newborn, but more broadly it includes development of diseases later in life including diabetes, hypertension, and coronary artery disease.

ORGANISM(S): Ovis Aries Sheep

TISSUE(S): Adipose Tissue

DISEASE(S): Maternal Hypoxemia

SUBMITTER: Sean Wilson

PROVIDER: ST002043 | MetabolomicsWorkbench | Wed Dec 01 00:00:00 GMT 2021

REPOSITORIES: MetabolomicsWorkbench

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Project description:Intrauterine growth restriction (IUGR) affects up to 10% of pregnancies and often results in short- and long- term sequelae for offspring, including risk for adult cardiovascular disease (CVD). The mechanisms underlying IUGR are poorly understood, though poor blood flow and oxygen/nutrient provision to the IUGR fetus are thought to be the common endpoints of disease. Though several animal models of IUGR exist, few demonstrate later phenotypes of CVD despite a large body of evidence in humans linking IUGR and adult CVD onset. We thus hypothesized that in murine pregnancy, maternal late gestational hypoxia (LG-H) exposure resulting in IUGR would result in (1) adult phenotypes of CVD in hypoxia-exposed offspring, and (2) the placental transcriptome will demonstrate alterations that can be linked to risk of later disease. After subjecting pregnant mice to hypoxia (10.5% oxygen) from gestational day (GD) 14.5 to 18.5, we collected placentas at GD19. We examined RNA isolated from these placentas to perform RNA sequencing and analysis. Functional gene and cluster-based analysis suggest multiple changes in structural and functional genes important for placental health, with the top dysregulation involving vascular and metabolic pathways. Concordantly, a ~ 10% decrease in birthweights and ~30% decrease in litter size after LG-H (p<0.05) was observed, suggesting an environment of placental insufficiency. We also found that offspring exposed in-utero to LG-H exhibit CVD at 4 months of age, with males being worse than females, supporting developmental programming. Specifically, males exhibit increased body weight and an enlarged heart size, whereas both males and females develop hypertension, elevated abdominal fat, elevated leptin and elevated total cholesterol levels with aging. In summary, LG-H exposure in the pregnant mouse mimics human placental insufficiency related IUGR. The placentas of these exposed fetuses demonstrate a transcriptional response to the stressor of gestational hypoxia and predicts cardiovascular and metabolic effects that culminate into hypertension and adiposity with dyslipidemia.

Dataset Information

Maternal Hypoxemia and Oxidative Stress

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