Chronic Stress Exacerbates Long-term Microvascular Network Dysfunction Following Brain Trauma

Background: Preexisting factors are among the strongest predictors of recovery following traumatic brain injury (TBI), with chronic stress closely associated with permanent disability and worse long-term outcomes. While chronic cerebrovascular dysfunction is linked to these poor trajectories, as impaired blood flow regulation drives secondary disease progression, the mechanisms regulating this vascular failure remain incompletely understood. Crucially, how premorbid chronic stress and TBI disrupt the fundamental coordination of the cerebrovascular network post-injury remains unknown. Methods: To elucidate this coordination at rest and in response to increased neuronal activity, we used a model of three repeated moderate closed cortical impacts comorbid with chronic stress induced by social isolation (SI) post-weaning. Our previously developed vascular analysis pipeline (NOVAS3D) was employed to estimate changes in vascular radii across cerebrovasculature proximal to neuronal activation. Arteries and veins were annotated in the imaged volumes to allow for blood flow simulations. Results: Using graph-based network analysis, we demonstrate that TBI, when compounded with chronic stress, critically disrupts the long-range coordination of the capillary network. Specifically, the functional coordination of radius changes between nearby, non-adjacent capillaries was reduced by 40{+/-}20% in TBI+SI mice relative to controls. Consequently, simulations estimated that the vascular networks in TBI{+/-}SI mice experienced a 68{+/-}7% reduction in arterial red blood cell velocity (VRBC) responses to neuronal activation. These network-wide impairments were fundamentally driven by severely blunted vessel reactivity, including a 28{+/-}7% decrease in the magnitude of arteriolar dilations and a 47{+/-}7% decrease in the magnitude of arteriolar constrictions. Conclusion: These findings provide a mechanistic foundation for worse clinical outcomes seen in TBI patients with comorbid chronic stress, identifying arteriolar reactivity and long-range capillary coordination as critical therapeutic targets to mitigate secondary injury and improve long-term recovery.