Mild traumatic brain injury promotes chronic cerebrovascular inflammation and glymphatic suppression

Repetitive exposure to mild traumatic brain injury (r-mTBI) increases the risk for chronic traumatic encephalopathy (CTE) and vascular contributions to cognitive impairment and dementia (VCID). Given the strong association between head trauma exposure, persistent inflammatory endothelial damage, and glymphatic impairment, we hypothesized that cerebrovascular inflammation following r-mTBI may play a causal role in mediating post-traumatic gliovascular dysregulation, and the development of VCID pathology. To provide insight into potential mechanisms and upstream regulatory factors, we first examined the gliovascular transcriptional profile in post-mortem chronic human mTBI and r-mTBI tissue. Experimental validation was performed in a mouse model of chronic r-mTBI using transcriptomic, ultrastructural, biochemical, and functional assessments. We observed chronic cerebrovascular inflammation following r-mTBI, characterized by cerebrovascular macrophage recruitment, eNOS dysregulation, oxidative stress, hypoxia, and mitochondrial damage. This coincided with a temporal shift in macrophage activation, resulting in the emergence of a chronic, pro-inflammatory, oxidative cerebrovascular profile. Notably, we showed that chronic r-mTBI also deteriorates the cerebrovascular basement membrane components that anchor astrocyte endfeet to the cerebrovasculature, manifesting in perivascular AQP4 mislocalization and glymphatic suppression. These results suggest that repetitive head trauma can induce robust, persistent endothelial dysfunction, inflammation, oxidative stress, and metabolic dysregulation, that disrupts perivascular waste elimination pathways at the gliovascular interface early in the post-injury disease process.