Protection of blood-brain barrier as a potential mechanism for enriched environments to improve cognitive impairment caused by chronic cerebral hypoperfusion

Abstract Background Chronic cerebral hypoperfusion causes damage to the brain’s white matter underpinning vascular cognitive impairment. Inflammation and oxidative stress have been proposed as key pathophysiological mechanisms of which the transcription factor Nrf2 is a master regulator. We hypothesised that white matter pathology, microgliosis, blood-brain barrier breakdown and behavioural deficits induced by chronic hypoperfusion would be exacerbated in mice deficient in the transcription factor Nrf2. Methods Mice deficient in Nrf2 (male heterozygote or homozygous for Nrf2 knockout) or wild-type littermates on a C57Bl6/J background underwent bilateral carotid artery stenosis (BCAS) to induce chronic cerebral hypoperfusion or sham surgery and survived for a further 6 weeks. White matter pathology was assessed with MAG immunohistochemistry as a marker of altered axon-glial integrity; alterations to astrocytes and microglia/macrophages were assessed with GFAP and Iba1 immunohistochemistry, and blood-brain barrier breakdown was assessed with IgG immunohistochemistry. Behavioural alterations were assessed using 8-arm radial arm maze, and alterations to Nrf2-related and inflammatory-related genes were assessed with qRT-PCR. Results Chronic cerebral hypoperfusion induced white matter pathology, elevated microglial/macrophage levels and blood-brain barrier breakdown in white matter tracts that were increased in Nrf2+/− mice and further exacerbated by the complete absence of Nrf2. Chronic hypoperfusion induced white matter astrogliosis and induced an impairment in behaviour assessed with radial arm maze; however, these measures were not affected by Nrf2 deficiency. Although Nrf2-related antioxidant gene expression was not altered by chronic cerebral hypoperfusion, there was evidence for elevated pro-inflammatory related gene expression following chronic hypoperfusion that was not affected by Nrf2 deficiency. Conclusions The results demonstrate that the absence of Nrf2 exacerbates white matter pathology and microgliosis following cerebral hypoperfusion but does not affect behavioural impairment.

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Cilostazol reduces blood brain barrier dysfunction, white matter lesion formation and motor deficits following chronic cerebral hypoperfusion

Brain Research ◽

10.1016/j.brainres.2016.06.036 ◽

2016 ◽

Vol 1646 ◽

pp. 494-503 ◽

Cited By ~ 21

Author(s):

Hamidreza Edrissi ◽

Sarah C. Schock ◽

Robert Cadonic ◽

Antoine M. Hakim ◽

Charlie S. Thompson

Keyword(s):

White Matter ◽

Blood Brain Barrier ◽

White Matter Lesion ◽

Chronic Cerebral Hypoperfusion ◽

Brain Barrier ◽

Cerebral Hypoperfusion ◽

Motor Deficits ◽

Barrier Dysfunction ◽

Lesion Formation ◽

Blood Brain

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Reduction of Pericyte Coverage Leads to Blood-Brain Barrier Dysfunction Via Endothelial Transcytosis Following Chronic Cerebral Hypoperfusion

10.21203/rs.3.rs-168757/v1 ◽

2021 ◽

Author(s):

Zhengyu Sun ◽

Chenhao Gao ◽

Dandan Gao ◽

Ruihua Sun ◽

Wei Li ◽

...

Keyword(s):

Brain Damage ◽

Blood Brain Barrier ◽

Serum Proteins ◽

Chronic Cerebral Hypoperfusion ◽

Brain Barrier ◽

Cerebral Hypoperfusion ◽

Transmission Electron Microscopy Data ◽

Pericyte Coverage ◽

Blood Brain ◽

Post Operation

Abstract Background: Chronic cerebral hypoperfusion (CCH) is the leading cause for cerebral small vessel disease (CSVD). CCH is strongly associated with blood–brain barrier (BBB) dysfunction and white matter lesions (WML) in CSVD. But the effects of CCH on BBB integrity and constituents as well as the cellular and molecular mechanisms about the consequences of BBB dysfunction remain elusive. Whether maintaining BBB integrity can reverse CCH induced brain damage has also not been explored. Methods: In this study, we used a rat model of CSVD, established via permanent bilateral common carotid artery occlusion (2VO) to mimic the chronic hypoperfusive state of CSVD. The progression of BBB dysfunction and components of the BBB was assessed using immunostaining, western blotting and transmission electron microscopy. Data were analyzed using the one-way ANOVA test or two-tailed unpaired Student’s t tests.Results: We noted a transient yet severe breakdown of the BBB in the CC following CCH. The BBB was severely impaired as early as 1 day post operation and most severely impaired 3 days post operation. BBB breakdown preceded WML and neuroinflammatory responses. Moreover, pericyte loss was associated with BBB impairment and accumulation of serum proteins was mediated by increased endothelial transcytosis in the CC. BBB dysfunction led to brain damage by regulating TGF-β/Smad2 signaling. Further, protection of the BBB via inhibition of endothelial transcytosis ameliorated serum proteins leakage, microglial activation, oligodendrocyte progenitor cells (OPCs) activation and inappropriate TGF-β/Smad2 signaling activation. Conclusions: Our results indicate that reduced pericyte coverage leads to increased BBB permeability via endothelial transcytosis and protection of the BBB integrity ameliorates brain damage by regulating TGF-β/Smad2 signaling following CCH, therefore reversal of BBB dysfunction may be a promising strategy to treat CSVD.

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Experimental chronic cerebral hypoperfusion results in decreased pericyte coverage and increased blood–brain barrier permeability in the corpus callosum

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x17743670 ◽

2017 ◽

Vol 39 (2) ◽

pp. 240-250 ◽

Cited By ~ 17

Author(s):

Qinghai Liu ◽

Ryan Radwanski ◽

Robin Babadjouni ◽

Arati Patel ◽

Drew M Hodis ◽

...

Keyword(s):

Corpus Callosum ◽

Blood Brain Barrier ◽

Chronic Cerebral Hypoperfusion ◽

Brain Barrier ◽

Cerebral Hypoperfusion ◽

Behavioral Deficits ◽

Pericyte Coverage ◽

Blood Brain ◽

Bilateral Carotid ◽

Bbb Permeability

Murine chronic cerebral hypoperfusion (CCH) results in white matter (WM) injury and behavioral deficits. Pericytes influence blood–brain barrier (BBB) integrity and cerebral blood flow. Under hypoxic conditions, pericytes detach from perivascular locations increasing vessel permeability and neuronal injury. This study characterizes the time course of BBB dysfunction and pericyte coverage following murine experimental CCH secondary to bilateral carotid artery stenosis (BCAS). Mice underwent BCAS or sham operation. On post-procedure days 1, 3, 7 and 30, corpus callosum BBB permeability was characterized using Evans blue (EB) extravasation and IgG staining and pericyte coverage/count was calculated. The BCAS cohort demonstrated increased EB extravasation on postoperative days 1 ( p = 0.003) 3 ( p = 0.002), and 7 ( p = 0.001) when compared to sham mice. Further, EB extravasation was significantly greater ( p = 0.05) at day 3 than at day 30 in BCAS mice. BCAS mice demonstrated a nadir in pericyte coverage and count on post-operative day 3 ( p < 0.05, compared to day 7, day 30 and sham). Decreased pericyte coverage/count and increased BBB permeability are most pronounced on postoperative day 3 following murine CCH. This precedes any notable WM injury or behavioral deficits.

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