microRNAs in Preeclampsia

The first study on microRNAs (miRs) in preeclampsia was published in 2007. In this study, the expression levels of a subset of 157 miRNAs expressed in the placenta were tested by qRT-PCR in human placental samples from pregnancies without any complications, with PE, and with PE and small for gestational age (SGA) outcomes. 153 miRNA were detected in the placenta RNA samples and three of them were found to be upregulated in PE: miR-210, miR-155, miR-200b [255]. The first global transcriptomic analysis of microRNAs was performed with 20 PE placental samples and 20 controls, with microarray technology by Zhu and collaborators in 2009. Comparing gene expression profiles of the severe PE group with controls, 11 microRNAs were upregulated and 23 downregulated. Among them, many microRNAs are organized in chromosomal clusters: downregulated clusters are found in 13q31.3, 14q32.31, Xq26.2, Xq26.3, while upregulated clusters are found in 19q13.42 suggesting co-regulation profiles [256]. An integrative analysis was conducted comparing distinct datasets with the aim of identifying microRNAs–transcripts regulatory networks in preeclampsia. resulting in the construction of a map of putative microRNA-gene target interactions in developmental process, response to nutrient levels, cell di fferentiation, cell junction, membrane components [257].

Although many studies followed, most of them aimed at identifying di fferentially expressed miRs in placenta and in plasma samples from PE women. Fewer studies have focused in other cell types present in the placenta. For example, in fetal endothelial cells downregulation of miR-29a-3p and miR-29c-3p and upregulation of miR-146a is observed in PE patients [258]. Both miR-29a and miR-29c show proangiogenic functions by stimulating HUVECs proliferation and tube formation through VEGFA-induced and FGF2-induced cell migration pathways [259]. However, other studies sugges<sup>t</sup> an antiangiogenic role of miR-29c through downregulation of the IGF-1 proteins at the post-transcriptional level [260,261]. On the other hand, miR-146a inhibits the de-novo formation of blood vessels in-vitro and reduces tube formation ability in HUVECs [260,261]. The study of the role that miRs may have in the di fferent cell types present in the placenta is indispensable to understand the role of this molecules in the development of the disease. In the long term, it has also been shown that miRNA profiles in the neonate is altered following an hypertensive pregnancy; for instance the level of mir-146a at birth predict microvascular development three months later [262].

Many studies followed, aimed at identifying di fferentially expressed miRs in placenta and in plasma samples from PE women.

In this review, we will discuss the most well characterized microRNAs miR-210, miR-155 and give an overview of some of the research that has been carried out on circulating microRNAs, given their potential as clinically relevant biomarkers.
