Endothelial-Derived Extracellular Vesicles Induce Cerebrovascular Dysfunction in Inflammation

Roig-Carles, David; Willms, Eduard; Fontijn, Ruud D.; Martinez-Pacheco, Sarai; Mäger, Imre; de Vries, Helga E.; Hirst, Mark; Sharrack, Basil; Male, David K.; Hawkes, Cheryl A. and Romero, Ignacio A. (2021). Endothelial-Derived Extracellular Vesicles Induce Cerebrovascular Dysfunction in Inflammation. Pharmaceutics, 13(9), article no. 1525.

DOI: https://doi.org/10.3390/pharmaceutics13091525

Abstract

Blood–brain barrier (BBB) dysfunction is a key hallmark in the pathology of many neuroinflammatory 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 microvascular cells (hCMEC/D3) were treated with TNFα and IFNy, and the EVs were isolated and characterised. 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 analysed 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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