Secretion of sFLT1 and sENG into the maternal circulation

Preeclampsia complicates 5-7% of all pregnancies and is a major cause of maternal and perinatal morbidity and mortality worldwide. Aberrant expression of angiogenic modulators is important in the pathogenesis of preeclampsia. Studies have shown that maternal circulating levels of placenta-derived anti-angiogenic proteins such as a shortened endoglin (sENG) and soluble fms-like tyrosine kinase 1 receptor (sFLT1) are significantly higher in pregnancies complicated by preeclampsia than in normotensive control pregnancies. The precise mechanism(s) responsible for processing and shedding of these anti-angiogenic factors by the syncytiotrophoblast (ST) layer and their mode of transport in the maternal circulation remains elusive. Therefore, we have isolated and characterized ST-derived (CD63 and PLAP positive) exosomes from maternal plasma of preeclamptic (n=6) and normotensive (n=6) pregnancies. The exosomes were then assayed for the presence of sENG, ALK5 (a type I TGFβ receptor) and sFLT1. In preeclampsia, shortened ENG and ALK5 were present in the exosomes while sFLT1 was absent. ALK5 was also present in the circulating exosomes of normotensive controls but sENG was undetectable. These findings suggest that the sENG is secreted by ST cells into the maternal circulation via exosomes where it interacts with ALK5, allowing for TGFβ binding thereby interfering with its signaling. In contrast, sFLT1 is released by ST into the blood torrent as a soluble protein.