Systemic Extracellular Vesicles in Severe Early-Onset Preeclampsia Inhibit Angiogenesis in a Dose-Dependent Manner

BACKGROUND: Extracellular vesicles have been shown to be elevated in preeclampsia and capable of effecting endothelial cell dysfunction. Severe early-onset preeclampsia is a major pregnancy-specific condition and is strongly with angiogenic dysfunction. Thus, we sought to determine how extracellular vesicles from stratified severe early-onset preeclampsia patients impacted angiogenic function. METHODS: Systemic maternal plasma extracellular vesicles were isolated and analyzed by Western blot and nanoparticle tracking analysis. The impact of healthy pregnant control and severe early-onset preeclamptic extracellular vesicles was assessed in human umbilical vein endothelial cells to determine the effects on cell migration, angiogenic tube formation, and stress fiber formation. RESULTS: Severe early-onset preeclamptic extracellular vesicles were significantly elevated in maternal plasma compared with healthy pregnant controls. Increasing healthy pregnant control extracellular vesicles to levels seen in severe early-onset preeclampsia inhibited angiogenic function. Conversely, decreasing severe early-onset preeclampsia extracellular vesicles to levels seen in healthy pregnant controls restored angiogenic function. Furthermore, extracellular vesicle number dose-responsively impacted angiogenic tube formation. Although uptake of extracellular vesicles was evident in recipient cells, no transfer of extracellular vesicle-encapsulated proteins was detected. However, the addition of severe early-onset preeclamptic extracellular vesicles upregulated markers of disrupted endothelial barrier integrity and induced actin stress fiber formation. CONCLUSIONS: Our findings suggest that beyond a certain threshold, an elevation in the absolute number of circulating maternal extracellular vesicles induces endothelial dysfunction that could lead to hypertension and end-organ damage in severe early-onset preeclampsia.