Extracellular vesicles derived from dysfunctional cerebral endothelial cells of rats with vascular dementia impair oligodendrocyte function and myelination

Document Type

Conference Proceeding

Publication Date

1-29-2026

Publication Title

Stroke

Keywords

Brain, Vascular disease, Cerebrovascular disorders, Endothelial function, Vascular cognitive impairment

Abstract

Background: Cerebral vascular damage and white matter demyelination are hallmarks of vascular dementia (VaD), a major contributor to cognitive decline. Oligodendrocyte progenitor cells (OPCs) and oligodendrocytes (OLs) interact with cerebral endothelial cells (CECs), but how they communicate in VaD is unclear. Extracellular vesicles (EVs) mediate intercellular signaling via their bioactive cargo. This study tested the hypothesis that CEC-derived EVs (CEC-EVs) in VaD impair OL function and myelination. Methods: A multiple microinfarct (MMI) model was used to induce VaD in rats. Endogenous CEC-EVs were tracked using CEC specific CD63 reporter mice (CEC-CD63, Slco1c1-CreERT2; CD63/GFPflox). Primary CECs isolated 7 days post-MMI (MMI-CECs) or from sham controls were cultured. The in vivo and in vitro blood–brain barrier (BBB) integrity was evaluated using albumin and fibrin staining, and FITC–dextran permeability assay, respectively. EVs were isolated from the cultured CECs by ultracentrifugation (MMI-CEC-EVs). Human OPCs (hOPCs) were treated with MMI-CEC-EVs or vehicle control, and RNA sequencing was performed to assess gene expression. Results: MMI significantly increased extravascular albumin and fibrin deposition in the corpus callosum and striatum (p<0.05, n=3-5), while MMI-CECs exhibited 37% greater permeability than those from sham (p<0.05), indicating BBB disruption. Immunohistochemistry (IHC) showed that MMI significantly reduced the number of nerve/glial antigen 2 (NG2)+ OPCs and adenomatous polyposis coli (APC)+ mature OLs in the corpus callosum as well as the density of myelin binding protein (MBP) in the striatum (n=3, p<0.05), suggesting MMI-induced demyelination. In CEC-CD63 mice, IHC revealed that CD63/GFP-labeled EVs co-localized with OLs and OPCs in the corpus callosum, demonstrating endogenous CEC-EV communication with these cells. Compared to vehicle treatment, hOPCs treated with MMI-CEC-EVs showed impaired differentiation into myelinating OLs, with reduced APC+ and MBP+ cells (p<0.05, n=3). RNA sequencing analysis of hOPCs treated with MMI-CEC-EVs revealed that deregulated genes were highly associated with myelination, axon, glutamatergic synapse, and ion transport, suggesting the critical role of CEC-EVs in OL and neuronal dysfunction in VaD. Conclusions: MMI induces BBB disruption and demyelination. Dysfunctional CEC-EVs may impair OPC differentiation and OL function, linking vascular injury to white matter loss in VaD.

Volume

57

Issue

SUPPL_1

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