Circulating placental small extracellular vesicles miR-2110 depletion drives maternal-fetal endothelial injury in preeclampsia.

backgroundPreeclampsia (PE) is a leading cause of maternal and perinatal mortality. Placental dysfunction drives the onset of the condition through inadequate spiral artery remodeling and ischemia-hypoxia, triggering endothelial cell injury mediated by small extracellular vesicles (sEVs), which can increase long-term cardiovascular risk in both mothers and offspring. However, the mechanisms underlying this process remain unclear and unpredictable. Although placental sEVs carry dysfunctional miRNAs associated with endothelial injury, traditional methods of separation from plasma/explantations are subject to contamination and physiological irrelevance. Tissue-derived sEVs extracted by enzymatic digestion have higher fidelity but remain unexplored in the placenta and PE. PTPN14 (a tyrosine phosphatase regulating YAP1 nuclear exclusion) also inhibits endothelial function, but its role in PE remains unclear.

methodWe first established a rigorous pipeline based on combined enzymatic digestion to isolate high-purity, high-yield human placental tissue-derived sEVs (p-tsEV). A three-level exploration strategy was uniquely employed, combining sequencing and integrative analyses across p-tsEV, maternal circulating sEVs, and primary fetal umbilical endothelial cells (HUVECs). Mechanistic studies utilized human placenta tissue and primary HUVECs treated with p-tsEV, miRNA mimic/inhibitor-sEVs. We performed dual-luciferase reporter assays, cell function tests, and ROC analysis.

resultsPE p-tsEV significantly induced primary HUVECs injury. miR-2110 was the most reduced miRNA in PE p-tsEV and was validated in maternal plasma sEVs (P < 0.0001). Mechanistically, low levels of miR-2110 in PE decreased the direct binding inhibition of PTPN14, increased PTPN14 expression and inhibited YAP1 activation, down-regulated key molecules such as VEGFA and CD31, thereby affecting endothelial cell function. Supplementation with miR-2110-sEVs improves endothelial cell injury, while overexpression of PTPN14 reverses this effect. Additionally, reduced plasma sEVs miR-2110 levels at 16 weeks of gestation demonstrated excellent predictive efficacy for PE (AUC = 0.85).

conclusionWe first established the role of the miR-2110/PTPN14/YAP1 pathway regulatory network in PE endothelial cell injury. This mechanism links placental ischemia with endothelial cell injury and long-term cardiovascular risks in both mother and fetus. Our study provides a comprehensive understanding of the sEVs-mediated placenta-endothelium communication axis in PE, and miR-2110 serves as both a mechanistic mediator and an early diagnostic biomarker, offering new insights for targeted interventions and improving adverse outcomes.