Angiotensin II impairs the remyelination mediated by brain endothelial cell-derived exosomes.

White matter hyperintensities (WMH), characterized by myelin loss and axonal injury, are largely driven by hypertension, their most significant modifiable risk factor. The role of endothelial cell-derived exosomes (EC-Exos) in oligodendrocyte precursor cell (OPCs)-mediated remyelination within WMH remains critical but poorly defined. This study investigated the function of EC-Exos in remyelination by comparing exosomes from angiotensin II-treated brain microvascular endothelial cells (AngII-Exos; modeling hypertensive conditions) with those from untreated cells (BMEC-Exos; modeling normotensive conditions). In vitro, BMEC-Exos promoted OPCs differentiation, evidenced by increased myelin basic protein (MBP) expression and reduced immature NG2+ OPCs. AngII-Exos lost this pro-differentiation capacity, instead suppressing OPCs proliferation and inducing immature OPCs accumulation. In vivo, the focal demyelination mouse model showed that BMEC-Exos injected into the lateral ventricle migrated to lesions, enhancing MBP intensity and reducing NG2+ areas, while AngII-Exos failed to promote remyelination. Lipidomic analysis revealed AngII-Exos exhibited altered fatty acid profiles, including reduced levels of essential myelin-related lipids (e.g., FFA 18:1, 22:0) and elevated FFA 22:6, impairing their ability to supply lipid precursors for OPCs maturation. These findings demonstrate that Ang II disrupts EC-Exos lipid composition, compromising their pro-remyelination effects on OPCs, which may represent a critical pathological mechanism underlying hypertension-associated white matter damage. This study provides new mechanistic insights into vascular contributions to myelin repair and pathology.