Abstract
Preeclampsia is the most common placental pathology in pregnant females, with increased morbidity and mortality incurred on the mother and the fetus. There is a need for improved biomarkers for diagnosis and monitoring of this condition. Placental syncytiotrophoblasts at the maternal-fetal interface release nanoparticles, including extracellular microvesicles, into the maternal blood during pregnancy. Syncytiotrophoblast extracellular microvesicles (STEVs) are being studied for their diagnostic potential and for their potential physiologic role in preeclampsia. We hypothesized that STEV profiles in maternal circulation would be altered under conditions of preeclampsia compared to normal pregnancy. Extracellular vesicles (EVs) released by BeWo cells in vitro showed high expression of syncytin-1, but no plac1 expression, demonstrating that trophoblast cell EVs express syncytin-1 on their surface. Placental alkaline phosphatase also showed high expression on BeWo EVs, but due to concern for cross reactivity to highly prevalent isoforms of intestinal and bone alkaline phosphatase, we utilized syncytin-1 as a marker for STEVs. In vivo, syncytin-1 protein expression was confirmed in maternal plasma EVs from Control and Preeclampsia subjects by Western blot, and overall, lower expression was noted in samples from patients with preeclampsia (n = 8). By nanoparticle analysis, EV profiles from Control and Preeclampsia groups showed similar total plasma EV quantities (p = 0.313) and size distribution (p = 0.415), but STEV quantitative signal, marked by syncytin-1 specific EVs, was significantly decreased in the Preeclampsia group (p = 2.8 × 10−11). Receiver operating characteristic curve demonstrated that STEV signal threshold cut-off of <0.316 was 95.2% sensitive and 95.6% specific for diagnosis of preeclampsia in this cohort (area under curve = 0.975 ± 0.020). In conclusion, we report that the syncytin-1 expressing EV profiles in maternal plasma might serve as a placental tissue specific biomarker for preeclampsia.
Highlights
Preeclampsia is the most common placental pathology in pregnant females, with increased morbidity and mortality incurred on the mother and the fetus
We looked for expression of 3 placenta-specific proteins, syncytin-1, placental alkaline phosphatase (PLAP), and plac-1
Even though we found a general trend towards higher numbers of Extracellular vesicles (EVs) in preeclampsia subjects, we noted that there was a significant reduction in syncytiotrophoblast specific EV signal in preeclampsia maternal plasma samples
Summary
Preeclampsia is the most common placental pathology in pregnant females, with increased morbidity and mortality incurred on the mother and the fetus. Several groups have investigated the diagnostic and physiologic implications of maternal plasma microvesicles, including EVs, in normal pregnancy and in pregnancy-associated disorders These studies suggest that in addition to changes in total maternal plasma microvesicle pools, selective expression levels of circulating placental proteins may be altered in conditions of normal pregnancy versus pregnancy-associated disorders such as preeclampsia. In this context, three placental proteins, placental alkaline phosphatase (PLAP), syncytin-1, and syncytin-2 have been studied[19,26,27,28,29,30,31,32,33].
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