Mild traumatic brain injury induces pericyte detachment independent of stroke vulnerability.

Mild traumatic brain injury (mTBI) is an independent risk factor for ischemic stroke and can result in poorer outcomes- an effect presumed to involve the cerebral vasculature. Here we tested the hypothesis that mTBI-induced pericyte detachment from the cerebrovascular endothelium is responsible for worsened stroke outcomes. We performed a mild closed-head injury and/or treated C57/bl6 mice with imatinib mesylate, a tyrosine kinase inhibitor that induces pericyte detachment. The time course of pericyte detachment was assessed 7, 14, and 28 days post injury (DPI). To test the role of pericytes in TBI-induced exacerbation of ischemic stroke outcomes, we induced mTBI and/or treated mice with imatinib for one week prior to transient middle cerebral artery occlusion. We found that injury promoted pericyte detachment from the vasculature commensurate with the levels of detachment seen in imatinib-only treated animals, and that the detachment persisted for at least 14DPI, but recovered to sham levels by 28DPI. Further, mTBI, but not imatinib-induced pericyte detachment, increased infarct volume. Thus, we conclude that the transient detachment of pericytes caused by mTBI may not be sufficient to exacerbate subsequent ischemic stroke damage. These data have important implications for understanding cerebrovascular dysfunction following mTBI and potential mechanisms of increased risk for future ischemic strokes.

Mild Traumatic Brain Injury Induces Time- and Sex-Dependent Cerebrovascular Dysfunction and Stroke Vulnerability.

Mild traumatic brain injury (mTBI) produces subtle cerebrovascular impairments that persist over time and promote increased ischemic stroke vulnerability. We recently established a role for vascular impairments in exacerbating stroke outcomes 1 week after TBI, but there is a lack of research regarding long-term impacts of mTBI-induced vascular dysfunction, as well as a significant need to understand how mTBI promotes stroke vulnerability in both males and females. Here, we present data using a mild closed head TBI model and an experimental stroke occurring either 7 or 28 days later in both male and female mice. We report that mTBI induces larger stroke volumes 7 days after injury, however, this increased vulnerability to stroke persists out to 28 days in female but not male mice. Importantly, mTBI-induced changes in blood-brain barrier permeability, intravascular coagulation, angiogenic factors, total vascular area, and glial expression were differentially altered across time and by sex. Taken together, these data suggest that mTBI can result in persistent cerebrovascular dysfunction and increased susceptibility to worsened ischemic outcomes, although these dysfunctions occur differently in male and female mice.