Gelsolin is an endogenous inhibitor of syncytiotrophoblast extracellular vesicle shedding in pregnancy

Background Preeclampsia, a pregnancy-specific inflammatory disorder, is characterized by high levels of anti-angiogenic protein, soluble fms-like tyrosine kinase 1 (sFlt1), in the maternal circulation. sFlt1 producing molecular machinery is present in syncytiotrophoblast extracellular vesicles that are released by the placenta into maternal plasma during normal pregnancy, a process greatly accelerated in preeclampsia. We hypothesized that syncytiotrophoblast extracellular vesicles exposes cytoplasmic actin to plasma resulting in depletion of plasma gelsolin (pGSN), an abundant plasma protein that scavenges circulating actin and other pro-inflammatory mediators. Objective To test whether pGSN levels would be lower in preeclampsia and to assess whether recombinant human plasma gelsolin (rhpGSN) may promote placental health by decreasing shedding of syncytiotrophoblast extracellular vesicles. Methods We tested pGSN levels in third trimester plasma samples from women with preeclampsia and non-hypertensive pregnancies. We then assessed whether rhpGSN may act as a negative regulator of syncytial shedding in placental explant culture and dynamic mechanical stretch studies. Results pGSN levels fall in late pregnancy and decline further in preeclampsia patients. Recombinant human pGSN (rhpGSN) at 100 μg/ml limits spontaneous syncytiotrophoblast vesicle release and sFlt1 protein dissemination by normal placental explants. Higher rhpGSN doses (500 μg/ml) also limit syncytiotrophoblast vesicle and sFlt1 dissemination from preeclamptic placental explants. rhpGSN also mitigates syncytiotrophoblast vesicle during dynamic mechanical stretch. Conclusions 1) pGSN, an anti-inflammatory factor of maternal origin is reduced in preeclampsia and may contribute to disease progression and 2) exogenous rhpGSN supplementation can limit the dissemination of toxic syncytiotrophoblast vesicle that characterizes the disease state.