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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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.

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13 Oct 2021 14:55
Last Modified:
20 Sep 2023 01:46