SFlt-1-enriched exosomes induced endothelial cell dysfunction and a preeclampsia-like phenotype in mice. (June 2023)

• Record Type: Journal Article
• Authors: Huang, Xiaojie; Jia, Linyan; Jia, Yuanhui; Xu, Xianghong; Wang, Ruixue; Wei, Mengtian; Li, Han; Peng, Hao; Wei, Yingying; He, Qizhi; Wang, Kai
• Is Part Of: Cytokine. Volume 166(2023)
• Publication Date: 2023-06
• Subjects: Exosome -- sFlt-1 -- Preeclampsia -- Endothelial cell -- Dysfunction; PE Preeclampsia -- sFlt-1 soluble FMS-like tyrosine kinase-1 -- sFlt-1-Exo sFlt-1-enriched exosomes -- HUVEC human umbilical vein endothelial cell -- sEng soluble endoglin -- VEGFR1 vascular endothelial growth factor receptor-1 -- VEGF vascular endothelial growth factor -- PlGF placental growth factor -- eNOS endothelial nitric oxide synthase -- NO nitrogen monoxide -- FGF fibroblast growth factor -- DEPs differentially expressed proteins -- GO Gene Ontology -- STBEVs syncytiotrophoblast extracellular vesicles -- NEP neprilysin -- NAFT nuclear factor of activated T cells -- ATF3 activating transcription factor 3; Cytokines -- Periodicals; 571.844
• DOI: 10.1016/j.cyto.2023.156190
• Languages: English
• ISSNs: 1043-4666

Abstract

Graphical abstract: Highlights: sFlt-1 (soluble fms-like tyrosine kinase-1)-enriched exosome (sFlt-1-Exo) derived from sFlt-1 overexpressed trophoblast cells can induce endothelial cells dysfunction by promoting the expression and secretion of sFlt-1. sFlt-1-enriched exosome triggered a preeclampsia-like phenotype in mice at a very low dose. The sFlt-1 in exosomes derived from pregnant women was increased with gestational age. Abstract: Preeclampsia (PE) is a hypertensive disorder of pregnancy characterized by maternal endothelial dysfunction and end-organ damage. Our previous work demonstrated that PE patient-derived exosomes contained higher levels of soluble FMS-like tyrosine kinase-1 (sFlt-1) and significantly induced endothelial dysfunction and PE development. However, the mechanisms underlying the effect of sFlt-1-enriched exosomes (sFlt-1-Exo) on PE development are poorly characterized. Here, we revealed that trophoblast-derived sFlt-1-Exo treatment induced significant inhibition of human umbilical vein endothelial cell (HUVEC) migration and tube formation, as well as an increase in sFlt-1 secretion. Mechanistically, we found that the increased sFlt-1 secretion in the cell culture medium was attributed to enhanced transcription of sFlt-1 in HUVECs. Importantly, we observed that treating pregnant mice with sFlt-1-Exo or recombinant mouse sFlt-1 triggered a preeclampsia-like phenotype, characterized by elevated blood pressure, proteinuria, increased plasma sFlt-1 and adverse pregnancy outcomes. These results strongly suggested that sFlt-1-Exo-induced endothelial dysfunction could be partially attributed to the upregulation of sFlt-1 in endothelial cells, potentially leading to the development of a preeclampsia-like phenotype in mice.