MicroRNA Profiles of Maternal and Neonatal Endothelial Progenitor Cells in Preeclampsia

Abstract

Preeclampsia is associated with an increased cardiovascular morbidity of mother and offspring, thus contributing to a substantial burden in women and children’s health. It has been proven that endothelial progenitor cell (EPC) numbers and functional characteristics are impaired in cardiovascular disease and preeclampsia, although causative factors for the latter have remained elusive. MicroRNA (miRNA) modifications are a potential mechanism through which exposure to an altered environment translates into the development of chronic disease. In this study, we examined whether development of preeclampsia corresponds to alterations of miRNAs in maternal- and cord-blood-derived EPC. To test this end, we analyzed maternal and neonatal miRNAs via RNA sequencing from endothelial cells of preeclamptic and healthy controls in different cell culture passages. We were able to demonstrate differentially represented miRNAs in all groups. Hsa-miR-1270 showed significantly different levels in cord blood EPC from preeclampsia versus control and was negatively correlated with mRNA levels of its predicted targets ANGPTL7 and TFRC. Transfection with an hsa-miR-1270 inhibitor decreased the tube formation capacity and chemotactic motility but did not change proliferation in vitro. Target predictions and gene set enrichment analyses identified alternative splicing as a significantly enriched pathway for hsa-miR-1270. The top miRNAs in three other groups were predicted to target transcriptional and developmental pathways. Here, we showed for the first time significantly different levels of miRNAs and differently represented mRNA levels of predicted target genes in EPC derived from preeclampsia. Understanding the effects of preeclampsia on the epigenetic mechanisms of EPC will be crucial and may provide initial insights for further evaluation of the benefits of therapies targeting this cell population.

Downregulation of miR‐1270 mediates endothelial progenitor cell function in preeclampsia: Role for ATM in the Src/VE‐cadherin axis

“…We deliberately focused on fetal cord blood ECFC because they reflect fetal endothelial function and play an essential role in endothelial health, repair, and vasculogenesis making them an important tool for pharmaceutical intervention for offspring from preeclamptic pregnancies. Moreover, in our own studies, we have shown that ECFC maintain a stable miRNA profile up to passage 5 28 and remain their functional (normal ECFC) and dysfunctional (preeclamptic ECFC) characteristic ex vivo 13,14,47,48 and could therefore provide some insight into the long‐term cellular effects in the offspring. The results of this study shed light on the mechanisms mediating endothelial dysfunction after pregnancy and possibly causing the increased incidence of cardiovascular alterations in offspring after maternal preeclampsia.…”

“…Since ECFCs have similar function in adults, it is conceivable that comparable effects could play a role in mothers after preeclampsia. In our previous study, we show differences in the miRNA profile of maternal and fetal ECFC from preeclamptic compared to healthy pregnancies 28 . However, more extensive investigations on whether the dysregulated miRNAs of maternal ECFC also cause a functional restriction in maternal ECFC are still lacking.…”

“…36 Vice versa, a role for ATM in the regulation of the mTOR signaling pathway has been described. 37 Based on our previous miRNA profile study of preeclamptic ECFC, we additionally analyzed all dysregulated miRNAs from preeclamptic cases (for publication, see Brodowski et al 28 ) using TargetScan v.7.2 (http://www.targe tscan.org/vert_72/), MirWalk 2.0 (http://zmf.umm.uni-heide lberg.de/apps/zmf/mirwa lk2/), and DIANA-TarBase v.7.0 (http://diana.imis.athen a-innov ation.gr/Diana Tools/ index.php?r=tarba se/index) (accessed on May 15, 2020), which revealed that miR-1270 is predicted to bind ATM (Figure 3A). Therefore, we evaluated the protein and mRNA levels of ATM in preeclamptic ECFC.…”

“…27 Recently, we reported the downregulation of miR-1270 in cord blood ECFC in preeclampsia. 28 In other studies, it has been demonstrated that miR-1270 is involved in diverse biological processes such as cancer in vitro proliferation and migration 29 and tumor progression such as thyroid cancer. 30 We hypothesized that miR-1270 dysregulation contributes to vascular endothelial dysfunction occurring after preeclampsia via ATM activation which may drive the increased incidence of cardiovascular disease in offspring's after maternal preeclampsia.…”

Impact of offspring endothelial function from de novo hypertensive disorders during pregnancy: An evidence-based review

“…The age of the offspring involved in the studies varied greatly. There were a few different life stages, namely prenatal age (19th-37th week of gestation) (16), neonates (aged less than four weeks old) (17)(18)(19)(20)(21)(22)(23)(24)(25)(26), infants (aged 2-12 months old) (21), toddlers (aged 1-3 years old) (27), children (aged 5-12 years old) (27,28) and adolescent (aged 12-19 years old) (27). The study population also varied.…”