Endothelial β-Catenin Deficiency Causes Blood-Brain Barrier Breakdown via Enhancing the Paracellular and Transcellular Permeability
Open accessAbstract
Disruption of the blood-brain barrier (BBB) causes or contributes to neuronal dysfunction and several central nervous system (CNS) disorders. Wnt/β-catenin signaling is essential for maintaining the integrity of the adult BBB in physiological and pathological conditions, including stroke. However, how the impairment of the endothelial Wnt/β-catenin signaling results in BBB breakdown remains unclear. Furthermore, the individual contributions of different BBB permeability-inducing mechanisms, including intercellular junction damage, endothelial transcytosis, and fenestration, remains unexplored. Here, we induced β-catenin endothelial-specific conditional knockout (ECKO) in adult mice and determined its impact on BBB permeability and the underlying mechanism. β-catenin ECKO reduced the levels of active β-catenin and the mRNA levels of Wnt target genes in mice, indicating downregulation of endothelial Wnt/β-catenin signaling. β-catenin ECKO mice displayed severe and widespread leakage of plasma IgG and albumin into the cerebral cortex, which was absent in wild-type controls. Mechanistically, both the paracellular and transcellular transport routes were disrupted in β-catenin ECKO mice. First, β-catenin ECKO reduced the tight junction protein levels and disrupted the intercellular junction ultrastructure in the brain endothelium. Second, β-catenin ECKO substantially increased the number of endothelial vesicles and caveolae-mediated transcytosis through downregulating Mfsd2a and upregulating caveolin-1 expression. Interestingly, fenestration and upregulated expression of the fenestration marker Plvap were not observed in β-catenin ECKO mice. Overall, our study reveals that endothelial Wnt/β-catenin signaling maintains adult BBB integrity via regulating the paracellular as well as transcellular permeability. These findings may have broad applications in understanding and treatment of CNS disorders involving BBB disruption.
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Wnt/β-catenin signaling is a pathway critical for BBB maintenance via regulation of tight junction proteins such as claudin-1.
“These effects may be linked to APOE3Ch cargo, consistent with activation of Wnt/β‐catenin signaling in endothelial cells, 8 a pathway critical for BBB maintenance via regulation of tight junction proteins such as claudin‐1. 65 , 66”
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- Authors
- Hussain, B., Fang, C., Huang, X., Feng, Z., Yao, Y., Wang, Y., & Chang, J.
- Affiliations
- Chinese Academy of Sciences (CN)
- University of Hong Kong (HK)
- Corresponding author
- Chang, Junlei
- Venue
- Frontiers in Molecular Neuroscience
- Publisher
- Frontiers Media SA
- Published
- 2022-05-09
- Volume
- 15
- Pages
- 895429-895429
- ISSN
- 1662-5099 (ISSN-L)
- PMC
- PMC9125181
- OpenAlex
- W4229370747
- Cited by
- 59
- References
- 3
- Citations by year
- 2026: 16 · 2025: 13 · 2024: 20 · 2023: 8 · 2022: 2
- FWCI
- 3.77
- Type
- journal article
- Language
- en
- Update notices
- corrigendum (2024-04-04)
- Open access
- gold
- doi.org
- Licence
- Locations
- Frontiers in Molecular Neuroscience (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Natural Science Foundation of China (32170985, 81771293, 31900704)
- National Key Research and Development Program of China (2021YFA0910000)
- Science, Technology and Innovation Commission of Shenzhen Municipality (JCYJ20210324115800003, ZDSYS20190902093409851, SGLH20180625142404672)
- CAS-Croucher Funding Scheme for Joint Laboratories
- Topics
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion Transport and Channel Regulation
- Keywords
- blood-brain barrier, β-catenin, Wnt/β-catenin signaling, endothelial cells, conditional knockout, blood-brain barrier permeability, paracellular permeability, transcellular permeability, tight junctions, MFSD2A, caveolin-1, PLVAP, fenestration, plasma protein leakage, stroke
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