The Role of Endothelial Dysfunction associated with TBI and BCAS

Presenters/Authors(s)

Megan Alexander , Zach Weil , Kate Weil

Abstract or Description

Traumatic brain injury (TBI) remains one the leading causes of death and disability. People that experience a TBI are at a greater risk of long-term decline and are more vulnerable to neurodegeneration. Specifically, endothelial dysfunction is a central player of neurodegeneration and many neurovascular diseases. Recent data from our laboratory has shown that mice with experimental traumatic brain injury following a reduction in cerebral blood flow (BCAS; bilateral carotid artery occlusion) experience considerable changes to endothelial cell transcriptional activity compared to mice with normal blood flow. We tested the hypothesis that TBI, following cerebral blood flow reduction, worsens cerebrovascular endothelial dysfunction and contributes to poorer functional outcomes. We experimentally reduced cerebral blood flow (via BCAS) 30 days before performing a closed head injury. We used laser speckle flowmetry to measure cerebral blood flow of the mice over the course of the experiment, and additionally the Barnes’ Maze as an assay of spatial learning and memory. Finally, we collected forebrain tissue for single cell RNA sequencing. TBI independently reduced cerebral blood flow and activated the endothelium as indicated by increased expression of inflammatory cytokines and adhesion molecules. These endpoints were greatly exacerbated in mice that underwent both TBI and BCAS procedures. Moreover, TBI+BCAS mice exhibited greater changes in transcriptional activity of endothelial cells compared to the sham mice, specifically with increases in electron transport chain proteins and ribosomes. Particularly interesting, RNA sequencing showed increases in cell adhesion molecules and decreases in blood-brain barrier proteins, suggesting differential endothelial cell activation after TBI+BCAS. These data, in addition to previous findings regarding increased endothelial cell stress and increased metabolic demand following TBI, indicate a role for endothelial cell dysfunction after TBI. These data have important implications because patients with endothelial dysfunction are more susceptible to cardiovascular and neurodegenerative diseases.