Preeclampsia is a pregnancy-induced condition that impairs the mother’s health and results in pregnancy termination or premature delivery. Elevated levels of placenta-derived extracellular vesicles (pcEV) in the circulation have been consistently associated with preeclampsia, but whether these vesicles induce preeclampsia or are the product of preeclampsia is not known. Guided by a small cohort study of preeclamptic patients, we examined the impact of pcEV on the pathogenesis of preeclampsia in mouse models. We detected pcEV in pregnant C56BL/6J mice with a peak level of 3.8±0.9×107/mL at 17-18 days post-coitum. However, these pregnant mice developed hypertension and proteinuria only after being infused with vesicles purified from injured placenta. These extracellular vesicles released from injured placenta disrupted endothelial integrity and induced vasoconstriction. Enhancing the clearance of extracellular vesicles prevented the development of the extracellular vesicle-induced preeclampsia in mice. Our results demonstrate a causal role of pcEV in preeclampsia and identify microvesicle clearance as a new therapeutic strategy for the treatment of this pregnancy-associated complication.Preeclampsia is a pregnancy-induced pathology characterized by poor placentation and endothelial dysfunction. Its primary clinical presentations include new-onset hypertension and proteinuria that resolve or are significantly improved after delivery or pregnancy termination.1,2 Preeclampsia can progress into eclampsia, potentially resulting in maternal and fetal death. Extensive clinical and laboratory studies have demonstrated that preeclampsia is triggered by placenta-derived mediators3 produced after placental ischemia and reperfusion injury, which could result from placental spiral artery remodeling disorders.4,5 One of these mediators is placenta-derived extracellular vesicles (pcEV), which are released into the maternal circulation, typically reaching a peak level in late pregnancy.6–8 These pcEV are constitutively released during normal pregnancy and are necessary for inducing maternal adaptive changes such as tolerance.9 However, excessive shedding of pcEV often indicates placental pathologies that contribute to the pathogenesis of preeclampsia. Significantly elevated plasma levels of pcEV have been consistently associated with the development and severity of preeclampsia.10,11The pcEV found in patients with preeclampsia are heterogeneous in their cells of origin, size, and cargo contents, and thus possess diverse activities, some of which may not be apparent or detectable in their parental cells. Despite this heterogeneity, extracellular vesicles (EV) from syncytiotrophoblasts are widely used as the surrogate marker for detecting pcEV in the maternal circulation,12,13 even though there is no evidence in the literature that these pcEV directly cause preeclampsia. Placental cells vesiculate when the placenta is subjected to ischemic and hypoxic injuries that result in cell apoptosis and tissue necrosis.14–17 These injuries can also occur when trophoblasts are unable to infiltrate the wall of the placenta’s spiral artery to gradually replace the endothelium in a process called “blood vessel recasting”.14–17Once released into the circulation, pcEV can cause endothelial injury,18–20 systemic inflammation,21,22 and coagulation dysfunction,23 all of which are hallmark events of preeclampsia. Despite extensive studies on the causes and mechanisms of placental injuries, key questions remain as to whether pcEV released from injured placenta directly induce the hypertension and proteinuria that define preeclampsia or are merely the products of preeclampsia. If the former holds true, could accelerating or enhancing the clearance of pcEV prevent preeclampsia or reduce its severity? Here we report the results of a study designed to answer these questions by analyzing blood samples from preeclamptic patients, studying new mouse models of preeclampsia, and conducting in vitro experiments.
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