Endothelial-derived extracellular vesicles induce cerebrovascular dysfunction in inflammation

Roig-Carles, D. and Willms, E. and Fontijn, R.D. and Martinez-Pacheco, S. and Mäger, I. and de Vries, H.E. and Hirst, M. and Sharrack, B. and Male, D.K. and Hawkes, C.A. and Romero, I.A. (2021) Endothelial-derived extracellular vesicles induce cerebrovascular dysfunction in inflammation. Pharmaceutics, 13 (9). ISSN 1999-4923

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Abstract

Blood–brain barrier (BBB) dysfunction is a key hallmark in the pathology of many neu-roinflammatory disorders. Extracellular vesicles (EVs) are lipid membrane-enclosed carriers of molecular cargo that are involved in cell-to-cell communication. Circulating endothelial EVs are increased in the plasma of patients with neurological disorders, and immune cell-derived EVs are known to modulate cerebrovascular functions. However, little is known about whether brain endothelial cell (BEC)-derived EVs themselves contribute to BBB dysfunction. Human cerebral micro-vascular cells (hCMEC/D3) were treated with TNFα and IFNy, and the EVs were isolated and char-acterised. The effect of EVs on BBB transendothelial resistance (TEER) and leukocyte adhesion in hCMEC/D3 cells was measured by electric substrate cell-substrate impedance sensing and the flow-based T-cell adhesion assay. EV-induced molecular changes in recipient hCMEC/D3 cells were an-alysed by RT-qPCR and Western blotting. A stimulation of naïve hCMEC/D3 cells with small EVs (sEVs) reduced the TEER and increased the shear-resistant T-cell adhesion. The levels of microRNA-155, VCAM1 and ICAM1 were increased in sEV-treated hCMEC/D3 cells. Blocking the expression of VCAM1, but not of ICAM1, prevented sEV-mediated T-cell adhesion to brain endothelia. These results suggest that sEVs derived from inflamed BECs promote cerebrovascular dysfunction. These findings may provide new insights into the mechanisms involving neuroinflammatory disorders.

Item Type:
Journal Article
Journal or Publication Title:
Pharmaceutics
Uncontrolled Keywords:
/dk/atira/pure/subjectarea/asjc/3000/3003
Subjects:
ID Code:
160638
Deposited By:
Deposited On:
13 Oct 2021 14:55
Refereed?:
Yes
Published?:
Published
Last Modified:
14 Oct 2021 05:45