sFlt-1-enriched exosomes induced endothelial cell dysfunction and a preeclampsia-like phenotype in mice

ElsevierVolume 166, June 2023, 156190CytokineAuthor links open overlay panel, , , , , , , , , , 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.

Keywords

Exosome

sFlt-1

Preeclampsia

Endothelial cell

Dysfunction

AbbreviationssFlt-1

soluble FMS-like tyrosine kinase-1

sFlt-1-Exo

sFlt-1-enriched exosomes

HUVEC

human umbilical vein endothelial cell

VEGFR1

vascular endothelial growth factor receptor-1

VEGF

vascular endothelial growth factor

PlGF

placental growth factor

eNOS

endothelial nitric oxide synthase

FGF

fibroblast growth factor

DEPs

differentially expressed proteins

STBEVs

syncytiotrophoblast extracellular vesicles

NAFT

nuclear factor of activated T cells

ATF3

activating transcription factor 3

© 2023 The Author(s). Published by Elsevier Ltd.

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