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Angiopoietin/Tie2 Axis Regulates the Age-at-Injury Cerebrovascular Response to Traumatic Brain Injury
- Source :
- The Journal of Neuroscience. 38:9618-9634
- Publication Year :
- 2018
- Publisher :
- Society for Neuroscience, 2018.
-
Abstract
- Although age-at-injury influences chronic recovery from traumatic brain injury (TBI), the differential effects of age on early outcome remain understudied. Using a male murine model of moderate contusion injury, we investigated the underlying mechanism(s) regulating the distinct response between juvenile and adult TBI. We demonstrate similar biomechanical and physical properties of naive juvenile and adult brains. However, following controlled cortical impact (CCI), juvenile mice displayed reduced cortical lesion formation, cell death, and behavioral deficits at 4 and 14 d. Analysis of high-resolution laser Doppler imaging showed a similar loss of cerebral blood flow (CBF) in the ipsilateral cortex at 3 and 24 h post-CCI, whereas juvenile mice showed enhanced subsequent restoration at 2–4 d compared with adults. These findings correlated with reduced blood–brain barrier (BBB) disruption and increased perilesional vessel density. To address whether an age-dependent endothelial cell (EC) response affects vessel stability and tissue outcome, we magnetically isolated CD31+ECs from sham and injured cortices and evaluated mRNA expression. Interestingly, we found increased transcripts for BBB stability-related genes and reduced expression of BBB-disrupting genes in juveniles compared with adults. These differences were concomitant with significant changes in miRNA-21-5p and miR-148a levels. Accompanying these findings was robust GFAP immunoreactivity, which was not resolved by day 35. Importantly, pharmacological inhibition of EC-specific Tie2 signaling abolished the juvenile protective effects. These findings shed new mechanistic light on the divergent effects that age plays on acute TBI outcome that are both spatial and temporal dependent.SIGNIFICANCE STATEMENTAlthough a clear “window of susceptibility” exists in the developing brain that could deter typical developmental trajectories if exposed to trauma, a number of preclinical models have demonstrated evidence of early recovery in younger patients. Our findings further demonstrate acute neuroprotection and improved restoration of cerebral blood flow in juvenile mice subjected to cortical contusion injury compared with adults. We also demonstrate a novel role for endothelial cell-specific Tie2 signaling in this age-related response, which is known to promote barrier stability, is heightened in the injured juvenile vasculature, and may be exploited for therapeutic interventions across the age spectrum following traumatic brain injury.
- Subjects :
- Male
0301 basic medicine
CD31
medicine.medical_specialty
Traumatic brain injury
Blood–brain barrier
Neuroprotection
Angiopoietin
Mice
03 medical and health sciences
0302 clinical medicine
Internal medicine
Brain Injuries, Traumatic
medicine
Animals
Juvenile
Research Articles
Cells, Cultured
Cerebral Cortex
biology
business.industry
General Neuroscience
Age Factors
medicine.disease
Receptor, TIE-2
Angiopoietin receptor
030104 developmental biology
Endocrinology
medicine.anatomical_structure
Cerebral blood flow
Blood-Brain Barrier
Cerebrovascular Circulation
biology.protein
business
030217 neurology & neurosurgery
Subjects
Details
- ISSN :
- 15292401 and 02706474
- Volume :
- 38
- Database :
- OpenAIRE
- Journal :
- The Journal of Neuroscience
- Accession number :
- edsair.doi.dedup.....bc870411e3eee4df2860e05caaf5830f