Abstract
Traumatic brain injury (TBI) has been associated with atherosclerosis and cardiovascular mortality in humans. However the causal relationship between TBI and vascular disease is unclear. This study investigated the direct role of TBI on vascular disease using a murine model of atherosclerosis. Apolipoprotein E deficient mice were placed on a western diet beginning at 10 weeks of age. Induction of TBI or a sham operation was performed at 14 weeks of age and mice were sacrificed 6 weeks later at 20 weeks of age. MRI revealed evidence of uniform brain injury in all mice subjected to TBI. There were no differences in total cholesterol levels or blood pressure between the groups. Complete blood counts and flow cytometry analysis performed on peripheral blood 6 weeks following TBI revealed a higher percentage of Ly6C-high monocytes in mice subjected to TBI compared to sham-treated mice. Mice with TBI also showed elevated levels of plasma soluble E-selectin and bone marrow tyrosine hydroxylase. Analysis of atherosclerosis at the time of sacrifice revealed increased atherosclerosis with increased Ly6C/G immunostaining in TBI mice compared to sham-treated mice. In conclusion, progression of atherosclerosis is accelerated following TBI. Targeting inflammatory pathways in patients with TBI may reduce subsequent vascular complications.
Highlights
Consistent with increased systemic endothelial adhesiveness, soluble E-selectin levels were higher in Traumatic brain injury (TBI) mice compared to sham-operated mice 6 weeks following the TBI (Fig. 6)
Cardiovascular complications following brain injury are not uncommon and include stress-related cardiomyopathy, arrhythmias, ECG repolarization changes, and increased cardiac reactive oxygen species[13]. These effects may be mediated by catecholamine surges as chronic and paroxysmal sympathetic hyperactivity are common after traumatic brain injury[14] and sympathetic overactivity is associated with chronic deleterious vascular effects[15]
Patients suffering myocardial infarction or stroke are at increased risk of a subsequent event within the first year following the incident event[17,18] and this is associated with elevated inflammatory biomarkers[19,20]
Summary
Blood pressure was measured 3 weeks after CCI or sham operation in non-anesthetized, trained mice by tail plethysmography using the BP-2000 Blood Pressure Analysis System (Visitech System, Apex, NC) as previously described[11]. Since brain injuries have been associated with surges of sympathetic activity that could affect blood pressure, tail-cuff plethysmography was used to measure blood pressure 3 weeks following injury in non-anesthetized mice. Immunostaining of bone marrow cross sections for myeloid markers revealed greater staining for proliferating cells and Ly6C/G positive cells in TBI mice compared to sham mice (Fig. 3).
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