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Regulatory small RNA profiling of first-trimester maternal plasma-derived exosome content in preeclampsia aggravated with intrauterine growth restriction

ABSTRACT: Preeclampsia (PE) is a pregnancy related multisystemic syndrome, which shows symptomes after the 20th week of the pregnancy. It affects 5-8% of all pregnancies, caused by placental disfunction and commonly combined with fetal intrauterine growth restriction (IUGR). Exosomes mediate cell-to-cell communication with their cargo, such as different types of RNA molecules. The exosomal RNA cargo is unique, gives information about the molecular condition of the donor cells and promotes altered gene expression in the acceptor cells. To address a better understanding of the pathophysiological mechanism of PE combined with IUGR, we investigated the differences of plasma exosomal regulatory small RNA content between healthy and PE+IUGR pregnancies before the development of symptoms. We created a high-throughput exosomal small RNA sequencing based method using first-trimester maternal plasma samples from 5 control and 5 PE+IUGR pregnancies to find differences in regulatory small RNA expression levels, such as miRNAs and piRNAs. The differential exosomal expression was corrected for the completed gestational weeks at sampling time calculated on the basis of the Crown-Rump Length (CRL). The analysis has shown differential exosomal expression in case of 16 miRNAs and 6 piRNAs in the PE+IUGR pregnancies compared to normal conditions (p-value ≤ 0.05) . All of the miRNAs and 3 piRNAs were up-regulated, wherease 3 piRNAs were down-regulated. Our results also supported the importance of gestational age at sampling time on exosomal small RNA expression.

ORGANISM(S): Homo sapiens

PROVIDER: GSE241815 | GEO | 2024/02/23

REPOSITORIES: GEO

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Project description:Preeclampsia (PE) is a peculiar multisystemic disorder that contributes to maternal and perinatal morbidity. Exosomes, existing in the circulation, origin from late endosomes which are secreted into the extracellular surrounding by diverse cell types under different conditions, can mediate intercellular communication via transporting its constituents and regulate inflammation, immunomodulation and angiogenesis. We hypothesize that exosomes from trophoblast in preeclampsia complications under pathological hypoxia microenvironment impair vascular development by transmitting its contents to endothelial cells. Here, transwell and tube formation assays revealed that exosomes from hypoxic trophoblast cells attenuated the migration, and tube formation in human umbilical vein endothelial cells (HUVECs) in vitro. In a mouse model, hypoxic trophoblast cells derived exosomes leaded to vascular dysfunction and caused adverse PE-like birth outcomes. Next, we detected lncRNA expression in cord blood plasma derived exosomes from gestational age-matched preeclampsia and normal pregnancies by microarray analysis. Then, we identified the possible mechanisms of one up-regulated exosomal lncRNA, TINCR. Application of Quantitative RT-PCR, lncTINCR was confirmed overexpressing in exosomes released from cord blood plasma, peripheral blood plasma and human placental trophoblasts of preeclampsia patients. Moreover, the exosomal lncTINCR could be specifically secreted by hypoxic trophoblast cells and transferred to HUVECs, which increased autophagy in HUVECs and impaired angiogenesis of endothelial cells in vitro. Furthermore, we demonstrated that lncTINCR was considered as a competing endogenous RNA to regulate miR-424, which resulted in elevated ATG5 expression. Thus, we reported that exosomes intervened effective delivering of lncTINCR to endothelial cells to damage vascular functions and result in the development of PE. The newly identified exosomal lncTINCR /miR-424/ATG5 axis may present potential novel targets of diagnosis and treatment for PE. lncRNA profiles of cord blood plasma derived exosomes from gestational age-matched preeclampsia and normal pregnancies

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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Regulatory small RNA profiling of first-trimester maternal plasma-derived exosome content in preeclampsia aggravated with intrauterine growth restriction

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