Blast-induced temporal alterations in blood–brain barrier properties in a rodent model

Abstract

The consequences of blast-induced traumatic brain injury (bTBI) on the blood–brain barrier (BBB) and components of the neurovascular unit are an area of active research. In this study we assessed the time course of BBB integrity in anesthetized rats exposed to a single blast overpressure of 130 kPa (18.9 PSI). BBB permeability was measured in vivo via intravital microscopy by imaging extravasation of fluorescently labeled tracers (40 kDa and 70 kDa molecular weight) through the pial microvasculature into brain parenchyma at 2–3 h, 1, 3, 14, or 28 days after the blast exposure. BBB structural changes were assessed by immunostaining and molecular assays. At 2–3 h and 1 day after blast exposure, significant increases in the extravasation of the 40 kDa but not the 70 kDa tracers were observed, along with differential reductions in the expression of tight junction proteins (occludin, claudin-5, zona occluden-1) and increase in the levels of the astrocytic water channel protein, AQP-4, and matrix metalloprotease, MMP-9. Nearly all of these measures were normalized by day 3 and maintained up to 28 days post exposure. These data demonstrate that blast-induced changes in BBB permeability are closely coupled to structural and functional components of the BBB.

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

“…Increased levels of brain MMP-9, MMP-9 mRNA, and plasma MMP-9 have been observed acutely after a 130-kPa blast exposure in association with blood–brain barrier dysfunction [ 66 ]. Gelatin zymography of purified cerebral vascular fractions showed that levels of MMP-2 and MMP-9 could also be increased at 6 weeks post-blast exposure (Fig.…”

“…Because gliovascular and neurovascular interactions control cerebral blood flow at multiple levels, their disruption following blast exposure would be expected to affect cerebral autoregulation. Morphological, biochemical and functional studies of humans and animal models have identified the vasculature as a primary target for blast-induced tissue damage [ 2 , 6 , 32 , 38 – 41 , 45 , 50 , 54 , 63 , 66 , 75 , 82 , 112 – 114 , 116 , 130 – 133 , 138 ]. Considerable evidence supports the concept of a thoracic effect whereby pressure waves transmitted through the systemic circulation damage the brain providing an additional mechanism for why blood vessels and perivascular cellular elements may be particularly susceptible to blast injury [ 116 , 117 ].…”

“…19 Summary timeline of cerebral pathological alterations in a rat model of blast-induced mild TBI. Shown are observations in blast-exposed animals from acute, subacute and chronic cohorts, all of which received 3 × 74.5 kPa exposures [ 2 , 39 – 41 , 63 , 66 , 67 ]. Acute, 24-72 h post-blast; Subacute, 6 weeks post-blast (normal behavioral phenotype); Chronic, 16–52 weeks post-blast, (PTSD-like behavioral phenotype) …”

“…The vertebral arteries that fuse into the basilary artery and its branches supply the remaining posterior and medial regions of the hemispheres, most of the diencephalon, brainstem, cerebellum, and cervical spinal cord. Blast exposure leads to prolonged impairment in vasoreactivity as well as changes in the structure, integrity and phenotype of cerebral blood vessels and astrocytes [ 2 , 40 , 63 , 66 ]. Localized blast-induced vascular injury may be a determinate of the brain areas where functional alterations will occur.…”

“…Direct consequences of blast exposure include acute damage and chronic structural degeneration of the cerebral vasculature. Early blast-induced vascular injury includes apoptosis of vascular structural elements, capillary strictures, vascular occlusion, blood–brain barrier disruption, vascular rupture, breakdown of the choroid plexus, reduced dilator responses to decreased intravascular pressure, reduced cerebral perfusion, and increased cerebral vascular resistance, [ 38 , 39 , 63 , 66 , 75 , 113 , 114 ]. These acute events are followed by the development of a chronic secondary pathology characterized by perivascular astrocytic degeneration, luminal collapse, disruption of neurovascular interactions, ECM remodelling, “double-barreled” vessels, intraluminal astrocytic processes, vascular smooth muscle degeneration, vascular occlusion by CD34 + progenitor cells, generalized vascular attenuation, aneurysm formation, vascular fragility and stroke [ 40 ].…”