Abstract
BackgroundThe placental syncytiotrophoblast releases micro and nanovesicles (STBM), into the maternal circulation in normal pregnancy and in increased amounts in pre-eclampsia (PE), which have proinflammatory and antiangiogenic activity and are implicated in PE pathophysiology. Better characterisation of STBM is essential to understand their role in PE.Methods and ResultsSTBM prepared by placental lobe dual perfusion (pSTBM) and mechanical disruption (mSTBM) were analysed by four colour flow cytometry (4CFC), nanoparticle tracking analysis (NTA) and Western blotting to determine vesicle size, purity and Flt-1 and endoglin (Eng) expression. Biological activity of STBM associated Flt-1 and endoglin was assessed by the ability of VEGF, PlGF and TGFβ to bind to mSTBM and inhibit mSTBM induced endothelial monolayer disruption. STBM content was consistently high (∼87–95%) across the different preparations. However, surface antigen intensities differed, with significantly lower placental alkaline phosphatase (P<0.05) and Eng (P<0.05) expression on mSTBM, and Flt-1 (P<0.05) expression on pSTBM. For PE placenta derived preparations, pSTBM contained lower Eng positive STBM (P<0.05) and mSTBM Eng expression was increased (P<0.05). Western blotting revealed increased Flt-1/sFlt-1 (P<0.02) and decreased placental alkaline phosphatase (P = 0.0002) content of PE placenta pSTBM. Using NTA, perfused PE placentas released significantly larger MV (P<0.001). Finally, VEGF, PlGF and TGFβ bound to mSTBM at physiologically relevant concentrations and inhibited mSTBM induced endothelial disruption (P<0.05-P<0.001).ConclusionsThis study has found differences in physical and antigenic characteristics of normal and PE placenta STBM preparations produced by placental perfusion or mechanical disruption. We have also demonstrated that large quantities of biologically active STBM associated endoglin and Flt-1/sFlt-1 could contribute to the increased circulating levels measured in PE patients and add to the perturbation of the maternal vascular endothelium, normally attributed to non-membrane bound sFlt-1 and sEndoglin.
Highlights
Pre-eclampsia (PE) is a complex disorder of human pregnancy, which causes maternal and perinatal mortality or morbidity, and has long-term health implications for mother and surviving offspring [1,2]
This study has found differences in physical and antigenic characteristics of normal and PE placenta syncytiotrophoblast releases micro and nanovesicles (STBM) preparations produced by placental perfusion or mechanical disruption
We have demonstrated that large quantities of biologically active STBM associated endoglin and fms-like tyrosine kinase 1 (Flt-1)/soluble Flt-1 (sFlt-1) could contribute to the increased circulating levels measured in PE patients and add to the perturbation of the maternal vascular endothelium, normally attributed to non-membrane bound sFlt-1 and sEndoglin
Summary
Pre-eclampsia (PE) is a complex disorder of human pregnancy, which causes maternal and perinatal mortality or morbidity, and has long-term health implications for mother and surviving offspring [1,2]. The second (clinical) stage (after 20 weeks) results from systemic vascular inflammation This has been shown to be an extension of a broader maternal systemic inflammatory response intrinsic to normal pregnancies, but more severe in pre-eclampsia, including endothelial dysfunction, and metabolic, clotting and complement disturbances. In searching for the cause of these changes in the mother in PE, our attention has focused on the role of syncytiotrophoblast derived vesicles (STBM). These are membrane bound vesicles shed from the syncytial epithelium (STB) of the placenta, that circulate during normal pregnancy and in significantly increased amounts in PE [5,6]. Better characterisation of STBM is essential to understand their role in PE
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