7 The antihypertensives, nifedipine and labetalol prevent endothelial cell activation in response to placental extracellular vesicles released from 1st trimester placental explants that had been treated with preeclamptic sera

Abstract

Objective Preeclampsia is a human pregnancy-specific disorder that presents as maternal hypertension and proteinuria after 20 weeks of gestation. Although the complete pathogenesis of preeclampsia is still unclear, previous studies have shown that placental extracellular vesicles shed from the syncytiotrophoblast into maternal circulation are associated with this disease. These vesicles can be categorised into macro- micro- and nano-vesicles based on their size. Previous studies have also shown that sera from women with preeclampsia changed the nature of placental macro-vesicles to become more dangerous/toxic such that they activated endothelial cells, but whether preeclamptic sera have the same effect on micro and nanovesicles is untested. In this study, we investigated whether preeclamptic sera affect the amount or nature of micro- and nano-vesicles extruded from first trimester placentae. We also investigated whether two drugs commonly used for symptom relief, nifiedipine or labetalol could reverse the activation of endothelial cells induced by these vesicles. Methods 1st trimester placental explants ( n = 8) were treated with 10% preeclamptic or control sera for 24 h. Micro- and nano-vesicles were harvested by sequential centrifugation at 20,000 g or 100,000 g for 1 h, respectively. The number of micro- or nano-vesicles was counted using a Nanosight (NS300) device. Micro- or nano-vesicles were exposed to monolayers of endothelial cells in the presence or absence of nifedipine (50 μg/ml) or labetalol (0.5 μg/ml). Cell-surface intercellular adhesion molecule 1 (ICAM-1) expression was measured by cell-based ELISA as a marker of endothelial cell activation. Results The amount of both micro- and nano-vesicles was significantly ( p p p = 0.004) or labetalol ( p = 0.002). Conclusion Our data demonstrate that an unknown factor(s) in preeclamptic sera causes an increase in the number of both micro- and nano-vesicles released from placentae which is consistent with the known increase in these vesicles in preeclampsia. The vesicles produced after treating placentae with preeclamptic sera were also more dangerous activating endothelial cells but this effect of the vesicles on endothelial cells is reversible by nifedipine or labetalol.