The Role of Extracellular Vesicles in the Pathogenesis of Preeclampsia

Jennifer Rogers

Introduction. Preeclampsia (PE), a hypercoagulable pregnancy disorder that involves multiple organs, is a leading cause of maternal and fetal mortality.1,2 PE is characterized by hypertension presenting after 20 weeks gestation, along with other symptoms, including proteinuria, thrombocytopenia, edema, and cerebral or visual changes.1,2 If PE remains untreated, it may progress to eclampsia, which involves seizure development.1 Placental dysfunction due to deficient spiral artery remodeling in the first 20 weeks is known to play a role in PE development, but the exact link is unknown.2 Understanding the pathogenesis of PE is crucial for developing effective treatment strategies. Current research into the presence and role of extracellular vesicles (EV), cell-derived membranous vesicles that contain biological material, during pregnancy may provide the missing link.3,4 Methods. A bovine endometrial intercaruncular stromal cell line was subjected to both hypoxic and normal oxygen tension levels.5 Plasma was obtained from third-trimester PE pregnancies and control-matched normotensive pregnancies.6 In both studies, the resulting EVs were isolated and quantified using centrifugation and nanoparticle tracking analysis.5,6 EVs taken from placentas of normal and PE pregnancies were incubated with healthy platelets and their interactions were analyzed using microscopy and fluorescence intensity.7 Finally, EVs taken from placentas of normal and PE pregnancies were injected into pregnant mice and pregnancy outcomes were analyzed.8 Results. Bovine cells subjected to hypoxia showed a 3.6-fold increase in EV production compared to cells subjected to normal oxygen tension.5 Pregnant women with PE were found to have significantly higher concentrations of circulating EVs than normotensive pregnant women.6 When in contact with EVs, platelets degranulate and internalize the EVs.7 PE EVs caused increased platelet activation and aggregation, and thrombus formation.7 Pregnant mice injected with PE EVs developed the hallmarks of PE.8 Furthermore, placentas of PE mice showed platelet accumulation which ultimately led to the activation of the inflammasome, a component of innate immunity that initiates a proinflammatory response.8 Conclusions. Early placental dysfunction due to hypoxia is directly responsible for the increase in EVs that is seen in PE. These altered EVs exert their effect on maternal platelets, which explains the characteristics of PE: platelet activation leads to a hypercoagulable state, platelet sequestration leads to thrombocytopenia, and the activation of proinflammatory factors leads to edema and renal dysfunction. Further therapeutic research should focus on how to target, inactivate, and eliminate these EVs in the hopes of mitigating the effects of PE.

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