Assessment of Cerebral Vascular Dysfunction After Traumatic Brain Injury

This study examined the effect of posttraumatic hypoxia on cerebral vascular responsivity and axonal damage, while also exploring hypothermia's potential to attenuate these responses. Rats were subjected to impact acceleration injury (IAI) and equipped with cranial windows to assess vascular reactivity to topical acetylcholine, with postmortem analyses using antibodies to amyloid precursor protein to assess axonal damage. Animals were subjected to hypoxia alone, IAI and hypoxia, IAI and hypoxia before induction of moderate hypothermia (33°C), IAI and hypoxia induced during hypothermic intervention, and IAI and hypoxia initiated after hypothermia. Hypoxia alone had no impact on vascular reactivity or axonal damage. Acceleration injury and posttraumatic hypoxia resulted in dramatic axonal damage and altered vascular reactivity. When IAI and hypoxia were followed by hypothermic intervention, no axonal or vascular protection ensued. However, when IAI was followed by hypoxia induced during hypothermia, axonal and vascular protection followed. When this same hypoxic insult followed the use of hypothermia, no benefit ensued. These studies show that early hypoxia and delayed hypoxia exert damaging axonal and vascular consequences. Although this damage is attenuated by hypothermia, this follows only when hypoxia occurs during hypothermia, with no benefit found if the hypoxic insult proceeds or follows hypothermia.

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Cerebral Vascular Injury in Traumatic Brain Injury

Experimental Neurology ◽

10.1016/j.expneurol.2015.05.019 ◽

2016 ◽

Vol 275 ◽

pp. 353-366 ◽

Cited By ~ 99

Author(s):

Kimbra Kenney ◽

Franck Amyot ◽

Margalit Haber ◽

Angela Pronger ◽

Tanya Bogoslovsky ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Vascular Injury ◽

Cerebral Vascular

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Rapid disruption of the cortical microcirculation after mild traumatic brain injury

10.1101/788455 ◽

2019 ◽

Author(s):

Ellen D. Witkowski ◽

Şefik Evren Erdener ◽

Kıvılcım Kılıç ◽

Sreekanth Kura ◽

Jianbo Tang ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Vascular Dysfunction ◽

Metabolic Stress ◽

Time Lapse ◽

Post Injury ◽

Injury Model ◽

Time Lapse Imaging

AbstractTraumatic brain injury (TBI) is a major source of cognitive deficits affecting millions annually. The bulk of human injuries are mild, causing little or no macroscopic damage to neural tissue, yet can still lead to long-term neuropathology manifesting months or years later. Although the cellular stressors that ultimately lead to chronic pathology are poorly defined, one notable candidate is metabolic stress due to reduced cerebral blood flow (CBF), which is common to many forms of TBI. Here we used high-resolution in vivo intracranial imaging in a rodent injury model to characterize deficits in the cortical microcirculation during both acute and chronic phases after mild TBI. We found that CBF dropped precipitously during immediate post-injury periods, decreasing to less than half of baseline levels within minutes and remaining suppressed for 1.5-2 hours. Repeated time-lapse imaging of the cortical microvasculature revealed further striking flow deficits in the capillary network, where 18% of vessels were completely occluded for extended periods after injury, and an additional >50% showed substantial stoppages. Decreased CBF was paralleled by extensive vasoconstriction that is likely to contribute to loss of flow. Our data indicate a major role for vascular dysfunction in even mild forms of TBI, and suggest that acute post-injury periods may be key therapeutic windows for interventions that restore flow and mitigate metabolic stress.

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Low-level blast exposure induces chronic vascular remodeling, perivascular astrocytic degeneration and vascular-associated neuroinflammation

Acta Neuropathologica Communications ◽

10.1186/s40478-021-01269-5 ◽

2021 ◽

Vol 9 (1) ◽

Author(s):

Miguel A. Gama Sosa ◽

Rita De Gasperi ◽

Dylan Pryor ◽

Georgina S. Perez Garcia ◽

Gissel M. Perez ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Vascular Remodeling ◽

Late Onset ◽

Neurovascular Unit ◽

Microcomputed Tomography ◽

Collagen Type Iv ◽

Post Traumatic Stress ◽

Type Iv ◽

Cerebral Vascular

AbstractCerebral vascular injury as a consequence of blast-induced traumatic brain injury is primarily the result of blast wave-induced mechanical disruptions within the neurovascular unit. In rodent models of blast-induced traumatic brain injury, chronic vascular degenerative processes are associated with the development of an age-dependent post-traumatic stress disorder-like phenotype. To investigate the evolution of blast-induced chronic vascular degenerative changes, Long-Evans rats were blast-exposed (3 × 74.5 kPa) and their brains analyzed at different times post-exposure by X-ray microcomputed tomography, immunohistochemistry and electron microscopy. On microcomputed tomography scans, regional cerebral vascular attenuation or occlusion was observed as early as 48 h post-blast, and cerebral vascular disorganization was visible at 6 weeks and more accentuated at 13 months post-blast. Progression of the late-onset pathology was characterized by detachment of the endothelial and smooth muscle cellular elements from the neuropil due to degeneration and loss of arteriolar perivascular astrocytes. Development of this pathology was associated with vascular remodeling and neuroinflammation as increased levels of matrix metalloproteinases (MMP-2 and MMP-9), collagen type IV loss, and microglial activation were observed in the affected vasculature. Blast-induced chronic alterations within the neurovascular unit should affect cerebral blood circulation, glymphatic flow and intramural periarterial drainage, all of which may contribute to development of the blast-induced behavioral phenotype. Our results also identify astrocytic degeneration as a potential target for the development of therapies to treat blast-induced brain injury.

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Cerebral vascular responsiveness after experimental traumatic brain injury: the beneficial effects of delayed hypothermia combined with superoxide dismutase administration

Journal of Neurosurgery ◽

10.3171/jns/2008/109/9/0502 ◽

2008 ◽

Vol 109 (3) ◽

pp. 502-509 ◽

Cited By ~ 19

Author(s):

Anna I. Baranova ◽

Enoch P. Wei ◽

Yuji Ueda ◽

Milton M. Sholley ◽

Hermes A. Kontos ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Superoxide Dismutase ◽

Free Radical ◽

Brain Injury ◽

Vascular Function ◽

Free Radical Scavengers ◽

Therapeutic Window ◽

Radical Scavenger ◽

Vascular Protection ◽

Cerebral Vascular

Object Traumatic brain injury (TBI) induces cerebral vascular dysfunction reflected in altered responses to vasodilators such as acetylcholine and hypercapnia. It has been demonstrated that the use of either posttraumatic hypothermia or free radical scavengers offered vascular protection when those treatments were delivered early after the injury, losing efficacy when the initiation of either treatment was delayed. Because immediate posttraumatic treatment is not realistic in the clinical setting, the authors undertook this study to investigate whether the combination of delayed hypothermia and the delayed administration of the free radical scavenger superoxide dismutase (SOD) could result in improved vascular protection. Methods Male Sprague–Dawley rats were anesthetized and subjected to either an impact-acceleration or sham injury. Animals were treated either with hypothermia (32°C) initiated 60 minutes after TBI, delayed SOD (60 U/ml) applied 90 minutes after TBI, or a combination of delayed hypothermia (32°C) and delayed SOD (60 U/ml) applied 15 minutes prior to the cessation of hypothermia. In this investigation, the diameter of cerebral pial arterioles was measured at rest and then challenged with vasodilator acetylcholine and hypercapnia. Four vessels were assessed per animal prior to injury and then again up to 6 hours after injury. Results Delayed SOD treatment did not enhance vascular function, while delayed hypothermia treatment only partially preserved pial vascular function. However, the combination of delayed hypothermia and delayed SOD significantly preserved vascular function after the injury. Conclusions The results of these studies demonstrate that delayed hypothermia partially preserves vascular function after TBI, while expanding the therapeutic window over which agents such as SOD can now provide enhanced protection.

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Juvenile Traumatic Brain Injury Induces Long-Term Perivascular Matrix Changes Alongside Amyloid-Beta Accumulation

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2014.124 ◽

2014 ◽

Vol 34 (10) ◽

pp. 1637-1645 ◽

Cited By ~ 18

Author(s):

Amandine Jullienne ◽

Jill M Roberts ◽

Viorela Pop ◽

M Paul Murphy ◽

Elizabeth Head ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Amyloid Beta ◽

Vascular Dysfunction ◽

Neurovascular Unit ◽

Early Brain Injury ◽

Glycoprotein P ◽

P Glycoprotein ◽

Blood Microvessels

In our juvenile traumatic brain injury (jTBI) model, emergence of cognitive dysfunctions was observed up to 6 months after trauma. Here we hypothesize that early brain injury induces changes in the neurovascular unit (NVU) that would be associated with amyloid-beta (Aβ) accumulation. We investigated NVU changes for up to 6 months in a rat jTBI model, with a focus on the efflux protein P-glycoprotein (P-gp) and on the basement membrane proteins perlecan and fibronectin, all known to be involved in Aβ clearance. Rodent-Aβ staining is present and increased after jTBI around cerebral blood microvessels, and the diameter of those is decreased by 25% and 34% at 2 and 6 months, respectively, without significant angiogenesis. P-glycoprotein staining in endothelium is decreased by 22% and parallels an increase of perlecan and fibronectin staining around cerebral blood vessels. Altogether, these results strongly suggest that the emergence of long-term behavioral dysfunctions observed in rodent jTBI may be related to endothelial remodeling at the blood–brain barrier alongside vascular dysfunction and altered Aβ trafficking. This study shows that it is important to consider jTBI as a vascular disorder with long-term consequences on cognitive functions.

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