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

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.

Preischemic Treadmill Exercise Ameliorates Memory Impairment and Microvasculature Damage in Rat Model of Chronic Cerebral Hypoperfusion

“…PDGFRβ plays an essential role in BBB functional recovery and integrity after BCCAO. BBB dysfunction is known to be caused by CCH-induced neuroinflammation and increased oxidative stress [27]. Therefore, the BBB could be a potential therapeutic target for cognitive impairment due to CCH-induced neuroinflammation, nerve damage, and increased oxidative stress [28,29].…”

Human ESC‐derived immunity‐ and matrix‐ regulatory cells ameliorated white matter damage and vascular cognitive impairment in rats subjected to chronic cerebral hypoperfusion

“…Using an electric drill, a burr hole to fix the tip of the LDF probe was made over the right parietal cortex (3 mm caudal from bregma and 5 mm lateral from the sagittal suture). The CCH model was established using the 2VO method as described previously 23 . Cerebral blood flow values were expressed as a percentage relative to the baseline value.…”

The role of inflammasomes in vascular cognitive impairment

“…In multiple mouse models of CCH, impairment of the BBB is observed through increased vascular permeability of intravascular Evans blue dye and horseradish peroxidase (HRP) into the brain parenchyma [ 91 , 98 , 99 ]. Several studies have also shown that CCH reduced pericyte coverage on capillaries, contributing to BBB dysfunction via endothelial transcytosis [ 91 , 100 , 101 ]. Moreover, the cerebrospinal fluid/plasma albumin ratio, another indicator of BBB damage, has also been reported to be elevated in VCI patients relative to healthy controls, with the severity of BBB damage corresponding to white matter lesions [ 102 ].…”

“…Despite an increase in inflammasome receptor mRNA expression, activation of the inflammasome complex was not detected in cerebral pericytes following exposure with a wide range of DAMPs [ 314 ]. However, as pericytes are increasingly implicated in BBB dysfunction during CCH [ 91 , 100 , 101 ], additional studies are needed to establish the role of inflammasomes in pericytes during VCI.…”