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.
AbstractPreeclampsia (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.
KeywordsExosome
sFlt-1
Preeclampsia
Endothelial cell
Dysfunction
AbbreviationssFlt-1soluble FMS-like tyrosine kinase-1
sFlt-1-ExosFlt-1-enriched exosomes
HUVEChuman umbilical vein endothelial cell
VEGFR1vascular endothelial growth factor receptor-1
VEGFvascular endothelial growth factor
PlGFplacental growth factor
eNOSendothelial nitric oxide synthase
FGFfibroblast growth factor
DEPsdifferentially expressed proteins
STBEVssyncytiotrophoblast extracellular vesicles
NAFTnuclear factor of activated T cells
ATF3activating transcription factor 3
© 2023 The Author(s). Published by Elsevier Ltd.
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