Abstract
Preeclampsia is a life-threatening hypertensive disease affecting 3-5% of pregnancies. While the pathogenesis of preeclampsia remains unclear, it is known that placenta-derived factors trigger the disease by activating maternal endothelial cells prior to the onset of clinical symptoms. Extracellular vesicles (EVs) of different sizes extruded by the placenta may be one factor. The truncated/secreted form of Flt-1 (sFlt-1) has also been implicated in the pathogenesis of preeclampsia. We investigated whether placental EV production is altered in preeclampsia such that they induce endothelial cell activation, and whether (s)Flt-1 is involved. Macro-, micro-, and nano-vesicles were collected from normal and preeclamptic (PE) placental explants, and separated by differential centrifugation. The number and size of micro- and nano-vesicles was measured by nanoparticle tracking analysis and their ability to activate endothelial cells was quantified by endothelial cell intercellular adhesion molecule 1 expression and monocyte adhesion. The levels of Flt-1 were measured by western blots and ELISA. PE placentae extruded significantly more micro- and nano-vesicles than control placentae and the extruded micro-vesicles were larger than those from control placentae. Micro- and nano-vesicles from both first trimester and term human placentae carried Flt-1 and levels were significantly increased in EVs from severe, but not mild, PE compared to normotensive placentae. All fractions of EVs from PE placentae activated endothelial cells, and for micro- and nano-vesicles, activation was reduced in the presence of exogenous vascular endothelial growth factor (VEGF), a Flt-1 neutralizing antibody, or by pre-treatment with VEGF. While EV-bound VEGF constituted over 20% of the total detected VEGF secreted by PE and normotensive placentae, EV-bound Flt-1 did not significantly contribute to the total level of sFlt-1/Flt-1 released by human third trimester placentae. Micro- and nano-vesicles extruded by human placentae carry Flt-1 across gestation and in severe preeclampsia, the levels of vesicle-bound Flt-1 are upregulated. All fractions of PE placental EVs activated endothelial cells and for micro- and nano-vesicles, this was in part due to the ability of EV-bound Flt-1 to sequester VEGF. That placental EVs can activate endothelial cells supports the contention that EVs are one placental toxin contributing to the pathogenesis of preeclampsia.
Highlights
Preeclampsia is a hypertensive disease unique to human pregnancy that causes significant maternal and fetal mortality and morbidity worldwide [1, 2]
In order to investigate whether the placental production of either micro- or nano-vesicles is affected in preeclampsia, micro- and nano-vesicles were collected from PE and normotensive placentae and their average sizes and concentrations were quantified by nanoparticle tracking analysis
In order to investigate whether extracellular vesicles (EVs) extruded from PE placentae can activate endothelial cells, cell-based ELISA of endothelial surface intercellular adhesion molecule 1 (ICAM-1) expression and monocyte adhesion assays were performed after exposure to macro, micro, and nano-vesicles from PE or control placentae for 24 h
Summary
Preeclampsia is a hypertensive disease unique to human pregnancy that causes significant maternal and fetal mortality and morbidity worldwide [1, 2]. Endothelial cell dysfunction is a central hallmark of preeclampsia that occurs prior to the onset of clinical signs [3,4,5,6]. While the pathogenesis of preeclampsia remains poorly understood, the placenta is known to play a crucial role as this disease can only occur in the presence of a placenta or a placental tumor [8, 9]. One vasoactive factor that has been proposed to play a central role in the pathogenesis of preeclampsia is soluble fmskinase 1 (sFlt-1) [10, 11]. The truncated version of Flt-1 is a soluble molecule that consists only of the ligand binding domain, allowing sFlt-1 to bind to VEGF/PlGF without downstream effects, effectively sequestering the growth factors [12]
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