Differential Blood–Brain Barrier Permeability Driven by Asymmetric Hypoperfusion in a Vascular Dementia Model

Background: Blood-brain barrier (BBB) dysfunction has been associated with vascular dementia (VaD). However, the underlying mechanisms causing BBB dysfunction remain unclear, especially regarding cerebral hypoperfusion. This study aims to investigate the effects of asymmetric hypoperfusion on BBB permeability using a mouse model of VaD. Methods: Asymmetric bilateral carotid artery stenosis (ACAS) was induced using ligature rings. BBB integrity was assessed on 3 days post-surgery using Evans blue, IgG and albumin extravasation. A modified tissue processing protocol optimized endogenous markers detection. Regional and sex-based differences in BBB permeability were analyzed. Results: Increased BBB permeability was observed in both corpus callosum and cortical areas, with significantly more severe leakage in the left cortex compared to the right, correlating directly with lower cerebral blood flow on the left side. In contrast, no significant asymmetrical difference in BBB permeability was detected in the corpus callosum. Additionally, male and female mice exhibited similar patterns of BBB permeability. Conclusion: This study provides the first evidence that asymmetrical hypoperfusion significantly impacts regional BBB permeability in a mouse model of VaD. These findings highlight the importance of local hemodynamic changes in driving BBB dysfunction and underscore potential therapeutic targets for preventing or mitigating vascular dementia progression.