Activation of Wnt signaling mitigates blood-brain barrier disruption by inhibiting vesicular transcytosis after traumatic brain injury in mice.

Autor: Zhang Y; Department of Neurosurgery, Nanchong Central Hospital, The Second Clinical Medical College of North Sichuan Medical College, Nanchong, China., Xu J; Neurosurgery of the Third People's Hospital of Mianyang/Sichuan Mental Health Center, Mianyang, 621000, Sichuan, China., Li P; Department of Neurosurgery, Nanchong Central Hospital, The Second Clinical Medical College of North Sichuan Medical College, Nanchong, China., Luo B; Department of Neurosurgery, Nanchong Central Hospital, The Second Clinical Medical College of North Sichuan Medical College, Nanchong, China., Tang H; Department of Neurosurgery, Nanchong Central Hospital, The Second Clinical Medical College of North Sichuan Medical College, Nanchong, China. Electronic address: hweitang@gmail.com.
Jazyk: angličtina
Zdroj: Experimental neurology [Exp Neurol] 2024 Jul; Vol. 377, pp. 114782. Date of Electronic Publication: 2024 Apr 18.
DOI: 10.1016/j.expneurol.2024.114782
Abstrakt: Elevated transport of Caveolin-1 (CAV-1) vesicles within vascular endothelial cells constitutes a significant secondary pathogenic event contributing to the compromise of the blood-brain barrier (BBB) post-traumatic brain injury (TBI). While Wnt/β-catenin signaling is recognized for its critical involvement in angiogenesis and the maintenance of BBB integrity, its influence on vascular endothelial transcytosis in the aftermath of TBI is not well-defined. This study aims to elucidate the impact of Wnt/β-catenin signaling on cerebrovascular vesicular transcytosis following TBI. In this experiment, adult male wild-type (WT) C57BL/6 mice underwent various interventions. TBI was induced utilizing the controlled cortical impact technique. Post-TBI, mice were administered either an inhibitor or an agonist of Wnt signaling via intraperitoneal injection. Recombinant adeno-associated virus (rAAV) was administered intracerebroventricularly to modulate the expression of the CAV-1 inhibitory protein, Major facilitator superfamily domain-containing 2a (Mfsd2a). This research utilized Evans blue assay, Western blot analysis, immunofluorescence, transmission electron microscopy, and neurobehavioral assessments. Post-TBI observations revealed substantial increases in macromolecule (Evans blue and albumin) leakage, CAV-1 transport vesicle count, astrocyte end-feet edema, and augmented aquaporin-4 (AQP4) expression, culminating in BBB disruption. The findings indicate that Wnt signaling pathway inhibition escalates CAV-1 transport vesicle activity and aggravates BBB compromise. Conversely, activating this pathway could alleviate BBB damage by curtailing CAV-1 vesicle presence. Post-TBI, there is a diminution in Mfsd2a expression, which is directly influenced by the modulation of WNT signals. Employing a viral approach to regulate Mfsd2a, we established that its down-regulation undermines the protective benefits derived from reducing CAV-1 transport vesicles through WNT signal enhancement. Moreover, we verified that the WNT signaling agonist LiCl notably ameliorates neurological deficits following TBI in mice. Collectively, our data imply that Wnt/β-catenin signaling presents a potential therapeutic target for safeguarding against BBB damage and enhancing neurological function after TBI.
Competing Interests: Declaration of competing interest The authors declare to have carried out the study in the absence of any commercial or financial relationship which might constitute a potential conflict of interest.
(Copyright © 2024 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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