Objective: Traumatic brain injury (TBI) is a common cause of morbidity and mortality in the veteran population. In the United States, there are an estimated 5.3 million people living with a TBI-related disability. TBI commonly leads to neurocognitive deficits, however, other systemic effects have also been associated with TBI. Cardiovascular effects include stress-related cardiomyopathy, arrhythmias, ECG repolarization changes, and increased cardiac reactive oxygen species. These effects may be mediated by catecholamine surges, although the mechanism(s) are unclear. In a clinical study of TBI in US veterans, TBI was strongly associated with the severity of coronary artery calcification as measured by electron beam computed tomography, suggesting TBI may promote processes involved in atherogenesis. Importantly, there was a marked independent association of TBI with cardiovascular mortality with a relative risk of 2.89 compared to a non-TBI control group, even after adjusting for typical cardiovascular risk factors. These observations indicate there may be a chronic and potent effect of TBI on atherosclerosis. However, whether these findings represent a direct link between TBI and systemic vascular changes or represent other confounding factors is unclear. The goal of this application is to determine the impact of TBI on vascular disease and to uncover underlying mechanisms responsible for these effects. Based on these results, therapeutic interventions will be tested in attempts to block the vasculopathic effects of TBI. Research Plan: To assess the effect of TBI in vascular disease processes, mouse models of TBI will be used to determine the effects of brain injury on sympathetic activity, vascular function, leukocyte-endothelial interactions and the development of atherosclerosis. Biomarkers and possible mediators will be measured through a combination of flow cytometry, liquid chromatography with tandem mass spectrometry, ELISA’s, magnetic resonance imaging, and histological analyses. Therapies designed to block activation of candidate adrenergic and downstream cytokine-triggered inflammatory pathways following TBI will be tested using relevant vascular endpoints. Methods: The strategy to accomplish the objectives will be to use in vivo mouse models, ex vivo, and in vitro assays to explore mediators of inflammation and vascular disease associated with TBI. Aim 1 will determine the effect of TBI on leukocyte-endothelial interactions and vascular function in atherosclerotic-prone mice.These endpoints will shed light on mechanisms related to the increased vascular risk associated with TBI. Aim 2 will explore mechanism(s) by which TBI promotes atherosclerosis by characterizing inflammatory responses, measuring catecholamines, and testing effects of adrenergic antagonists on vascular endpoints. Aim 3 will determine the role of downstream mediators, p-selecting glyocoprotein ligand-1, interleukin-1 receptor, and neutrophil extracellular traps (NETs) ...