Abstract
As the search for non-invasive preclinical markers of preeclampsia (PE) expands, the number of studies on the diagnostic potential of exosomes is growing. Changes in the partial pressure of oxygen caused by impaired uteroplacental perfusion in PE are a powerful inducer of increased production and release of exosomes from cells, which also determine their cargo. At the same time, the expression pattern of oxygen-dependent microRNAs (miRNAs), called “hypoxamiRs”, is modulated, and their packing into exosomes is strictly regulated by sumoylation. In connection therewith, we emphasize the evaluation of exosomal hypoxamiR expression (miR-27b-3p, miR-92b-3p, miR-181a-5p, and miR-186-5p) using quantitative RT-PCR, as well as SUMO 1–4 and UBC9 (by Western blotting), in pregnant women with early-onset PE. The findings show that miR-27b-3p and miR-92b-3p expression was significantly changed at 11–14 and 24–26 weeks of gestation in the blood plasma of pregnant women with early-onset PE, which subsequently manifested. High sensitivity and specificity (AUC = 1) were demonstrated for these miRNAs in the first trimester, and significant correlations with a decrease in hemoglobin (r = 0.71, p = 0.002; r = −0.71, p = 0.002) were established. In mid-pregnancy, the miR-27b-3p expression was found to correlate with an increase in platelets (r = −0.95, p = 0.003), and miR-92b-3p was associated with a decrease in the prothrombin index (r = 0.95, p = 0.003). Specific exomotifs of studied miRNAs were also identified, to which the sumoylated ribonucleoprotein hnRNPA2/B1 binds, carrying out their packaging into exosomes. The expression of conjugated SUMO 1 (p = 0.05), SUMO 2/3/4 (p = 0.03), and UBC9 (p = 0.1) was increased in exosomes at early-onset PE, and the expression of free SUMO 1 (p = 0.03) and SUMO 2/3/4 (p = 0.01) was significantly increased in the placenta, as an adaptive response to hypoxia. Moreover, SUMO 2/3/4 was negatively correlated with miR-27b-3p expression in the placenta. In conclusion, the diagnostic potential of exosomal hypoxamiRs mediated by sumoylation may form the basis for the development of combined specific targets for the treatment of early-onset PE, as hnRNPA2/B1 is a target of miR-27b-3p, and its sumoylation creates miR-27b-3p–hnRNPA2/B1–SUMO 1–4 cross-talk.
Highlights
In the context of great obstetric syndromes associated with the impaired transformation of uteroplacental vessels, preeclampsia (PE) continues to attract the close attention of researchers [1,2]
MiR-27b-3p, miR-92b-3p, miR-181a-5p, and miR-186-5p were selected for the experiment as we previously determined the altered expression in the peripheral blood plasma of pregnant women with early-onset PE during delivery
The expression of the above miRNAs was evaluated in exosomes of 16 pregnant women at gestational periods
Summary
In the context of great obstetric syndromes associated with the impaired transformation of uteroplacental vessels, preeclampsia (PE) continues to attract the close attention of researchers [1,2]. Progress in understanding the molecular processes associated with both the regulation of the normal development of the placenta and its dysfunction have made it possible to focus scientists on the study of the predictive role of microRNAs (miRNAs), which are small non-coding molecules that are epigenetic modulators of a significant number of biological processes [17]. Of particular importance, these can circulate in extracellular fluids as part of microvesicles, apoptotic bodies, and exosomes, acting as mediators of intercellular interactions and therapeutic targets in placenta-associated diseases [18,19]
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