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

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 associated with angiogenic dysfunction. Thus, we sought to determine how extracellular vesicles from stratified severe early-onset preeclampsia patients impacted angiogenic function.

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.

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.

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.