Abstract
Much concern exists over the role of blast-induced traumatic brain injury (TBI) in the chronic cognitive and mental health problems that develop in veterans and active duty military personnel. The brain vasculature is particularly sensitive to blast injury. The aim of this study was to characterize the evolving molecular and histologic alterations in the neurovascular unit induced by three repetitive low-energy blast exposures (3 × 74.5 kPa) in a rat model mimicking human mild TBI or subclinical blast exposure. High-resolution two-dimensional differential gel electrophoresis (2D-DIGE) and matrix-assisted laser desorption/ionization (MALDI) mass spectrometry of purified brain vascular fractions from blast-exposed animals 6 weeks post-exposure showed decreased levels of vascular-associated glial fibrillary acidic protein (GFAP) and several neuronal intermediate filament proteins (α-internexin and the low, middle, and high molecular weight neurofilament subunits). Loss of these proteins suggested that blast exposure disrupts gliovascular and neurovascular interactions. Electron microscopy confirmed blast-induced effects on perivascular astrocytes including swelling and degeneration of astrocytic endfeet in the brain cortical vasculature. Because the astrocyte is a major sensor of neuronal activity and regulator of cerebral blood flow, structural disruption of gliovascular integrity within the neurovascular unit should impair cerebral autoregulation. Disrupted neurovascular connections to pial and parenchymal blood vessels might also affect brain circulation. Blast exposures also induced structural and functional alterations in the arterial smooth muscle layer. Interestingly, by 8 months after blast exposure, GFAP and neuronal intermediate filament expression had recovered to control levels in isolated brain vascular fractions. However, despite this recovery, a widespread vascular pathology was still apparent at 10 months after blast exposure histologically and on micro-computed tomography scanning. Thus, low-level blast exposure disrupts gliovascular and neurovascular connections while inducing a chronic vascular pathology.
Highlights
Traumatic brain injury (TBI) has long been a major cause of combat-related disability [25]
A rat model of low-level blast injury We have been studying an animal model developed to mimic a level of blast exposure that would be associated with human mild TBI or a subclinical exposure
Because multiple blast exposures have been common among veterans returning from Iraq and Afghanistan [28], for most studies we used a design in which rats received three 74.5-kPa exposures delivered one exposure per day on 3 consecutive days
Summary
Traumatic brain injury (TBI) has long been a major cause of combat-related disability [25]. Public awareness of TBI in the military has increased recently due to events in Iraq and Afghanistan where 10–20% of veterans returning from these conflicts experienced a TBI [28]. While military related TBIs in Iraq and Afghanistan resulted from various mechanisms due to the wide spread use of improvised explosive devices, blast-related TBIs were most common [28]. In combat settings such as Iraq and Afghanistan, lower level exposures producing mTBIs have been much more common [28]. In addition there is increasing concern over the potential adverse consequences of subclinical blast exposures, which are common for many service members in non-combat settings [12]
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