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Gene expression profiling indicates inflammatory pathways involved in IUGR due to placental insufficiency

ABSTRACT: Intrauterine growth restriction (IUGR) represents a major obstetric challenge with perinatal complications and a risk factor of developing disease in adult life. Placental insufficiency is one of the common features accompanying IUGR. The aim of this study was to evaluate global placental gene expression profile in IUGR compared to normal pregnancies. Placental samples were collected by eight IUGR pregnancies with placental insufficiency ascertained by Doppler and eight healthy controls. A 30K Human Genome Survey Microarray v.2.0 (Applied Biosystems) was used to evaluate global gene expression profile. Principal component analysis showed good separation in terms of gene expression patterns between the groups. Pathway analysis with Bonferroni correction for multiple testing showed significant (p<0.05) up-regulation of inflammation mediated by chemokine and cytokine signalling pathway in the IUGR placentas. Genes involved in metabolism of glucocorticoids (HSD11B1 and DHRS2) were found differentially expressed. We found no imprinted genes to be differentially expressed and only one gene involved in epigenetic modifications (MBD3) to be down-regulated in the IUGR placentas, indicating that IUGR due to placental insufficiency is not associated to placental imprinting. Subgroup analysis between pure IUGR and IUGR with preeclampsia placentas showed only 27 differentially expressed genes suggesting common pathophysiology.

ORGANISM(S): Homo sapiens

PROVIDER: GSE12216 | GEO | 2008/08/01

SECONDARY ACCESSION(S): PRJNA113733

REPOSITORIES: GEO

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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.

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Gene expression profiling indicates inflammatory pathways involved in IUGR due to placental insufficiency

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