Blood–Brain Barrier Disruption in White Matter Lesions in a Rat Model of Chronic Cerebral Hypoperfusion

Abstract

Blood-brain barrier damage has been implicated in the pathogenesis of cerebrovascular white matter lesions. This type of lesion is responsible for cognitive impairment in the elderly and can be induced by permanent ligation of the bilateral common carotid arteries in the rat. Because it is unclear whether the blood-brain barrier is impaired, we examined whether vascular permeability to horseradish peroxidase is altered using this model. According to light microscopic results, the reaction product of horseradish peroxidase was most intensely localized to the paramedian part of the corpus callosum in the brain, occurring to a small degree at 3 hours, day 1, markedly on day 3, but reduced on days 7 and 14. By electron microscopic study of the same area, the reaction product of horseradish peroxidase was localized to the plasmalemmal vesicles in the endothelial cells 3 hours after ligation, but appeared in the cytoplasm on days 1 and 3, suggesting a diffuse leakage of horseradish peroxidase. In addition, the reaction product was dispersed into the cytoplasm of glial cells in the perivascular regions on day 3. The luminal surface of the endothelial cell cytoplasm appeared irregular on day 7, suggesting a conformational change of the endothelial cells. Collagen fibrils proliferated in the thickened basal lamina and mitochondria degenerated in the pericyte on days 7 and 14. Perivascular glial endfeet were swollen throughout the survival period. In sham-operated rats, the reaction product of horseradish peroxidase was not observed at any time interval, except in vesicular structures. These findings indicate that chronic cerebral hypoperfusion induces blood-brain barrier damage with subsequent morphologic changes of the vascular structures in the corpus callosum. An extravasation of macromolecules, such as proteases and immunoglobulins, may contribute to the pathogenesis of white matter lesions.

The expression of matrix metalloproteinase-13 is increased in vessels with blood–brain barrier impairment in a stroke-prone hypertensive model

“…27,28 In the rat model of chronic cerebral hypoperfusion, BBB function was disrupted in the white matter lesions. 3 These results suggest that increased expression of MMP-2 and MMP-9 induce increased BBB permeability followed by brain damage. In addition, it was reported using an MMP protein array that high levels of MMP-9 and MMP-13, also known as collagenase-3, are involved in diffusion-weighted image lesion growth.…”

“…1 To clarify the roles of BBB impairment in vascular dementia, we have examined BBB function in various conditions related to vascular dementia, such as hypertension, acute ischemia with reperfusion, chronic cerebral hypoperfusion and aging with or without memory deficits. [2][3][4] Consequently, among these animal models, the most localized BBB impairment was clearly seen in the hippocampus, but not the cerebral cortex, of 3-month-old spontaneously hypertensive rats (SHR), especially of 3-month-old stroke-prone SHR (SHRSP), 4 which were established by Okamoto and Aoki 5 and are described in detail elsewhere. 6,7 It is known that the neuronal loss occurs with a reduction of gray matter volume in the CA1 subfield and dentate gyrus of the hippocampus in SHR at the age of 6 months or order, indicating that SHR can be a good animal model of vascular dementia.…”

Consensus statement for diagnosis of subcortical small vessel disease

“…69,116 Bilateral Carotid Artery Occlusion Bilateral carotid artery occlusion (BCAO) produces hypoxic hypoperfusion, which primarily affects the deep white matter. 117 The tissue is assumed to be hypoxic although direct measurements of tissue oxygen levels have not been made. White matter shows demyelination with breakdown of the BBB; MMPs are expressed in the hypoxic tissue and contribute to the myelin damage.…”

Doin vivoExperimental Models Reflect Human Cerebral Small Vessel Disease? a Systematic Review

“…Bilateral common carotid occlusion ('2-VO') in rats produced a chronic reduction in cerebral blood flow by 50% to 70%; (Ni et al, 1994;Wakita et al, 1995Wakita et al, , 2002Ohta et al, 1997;Ueno et al, 2002). Lesions were predominantly in white matter, with vacuolation of myelin, axonal damage, and demyelination in corpus callosum, internal capsule, and caudateputamen.…”