Trophoblast-Derived Extracellular Vesicles Promote Preeclampsia by Regulating Macrophage Polarization
BACKGROUNDSystemic inflammation caused by dysfunctional macrophages is a crucial pathogenetic event in preeclampsia (PE). Trophoblast-derived extracellular vesicles (T-EVs) are potent immune cell signaling modulators in pregnancy. Herein, we aimed to investigate T-EVs' effect and mechanism on m...
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Veröffentlicht in: | Hypertension (Dallas, Tex. 1979) Tex. 1979), 2022-10, Vol.79 (10), p.2274-2287 |
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Sprache: | eng |
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Zusammenfassung: | BACKGROUNDSystemic inflammation caused by dysfunctional macrophages is a crucial pathogenetic event in preeclampsia (PE). Trophoblast-derived extracellular vesicles (T-EVs) are potent immune cell signaling modulators in pregnancy. Herein, we aimed to investigate T-EVs' effect and mechanism on macrophage polarization and its role in PE pathogenesis, which remain unclear. METHODSFlow cytometry and immunochemistry were used to determine placental macrophage phenotypes. T-EVs were immuno-isolated via placental alkaline phosphatase antibody and identified by transmission electron microscopy and nanoparticle tracking analysis. Quantitative real-time polymerase chain reaction and flow cytometry were used to examine the effects of T-EVs on macrophage polarization, and correlation analysis of T-EVs lipidomics and macrophages transcriptome were performed to explore how T-EVs modulate macrophages. Animal experiments were established to investigate the relationship among PE, T-EVs, and macrophages. RESULTSMacrophages shift from the M2 to M1 phenotype in the preeclamptic placenta. Also, T-EVs from women with PE (PE-EVs) significantly upregulated M1 gene markers and significantly downregulated CD163 expression in macrophages compared with T-EVs in women with normal pregnancies (NP-EVs). Mechanistically, correlation analysis with T-EVs lipidome and the transcriptome of macrophages treated with PE-EVs or NP-EVs indicated that 37 lipids altered in PE-EVs considerably affected classical inflammatory biological pathways in macrophages. Finally, animal experiments revealed that PE-EVs triggered PE-like symptoms in pregnant mice, which were alleviated after macrophage depletion. CONCLUSIONST-EVs from women with PE could promote preeclampsia by inducing macrophage imbalance polarization, signifying a potential novel interventional target for the prevention and management of PE. |
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ISSN: | 0194-911X 1524-4563 |
DOI: | 10.1161/HYPERTENSIONAHA.122.19244 |