VEGF-mediated disruption of endothelial CLN-5 promotes blood-brain barrier breakdown
Open accessAbstract
Breakdown of the blood-brain barrier (BBB) is an early and significant event in CNS inflammation. Astrocyte-derived VEGF-A has been implicated in this response, but the underlying mechanisms remain unresolved. Here, we identify the endothelial transmembrane tight junction proteins claudin-5 (CLN-5) and occludin (OCLN) as targets of VEGF-A action. Down-regulation of CLN-5 and OCLN accompanied up-regulation of VEGF-A and correlated with BBB breakdown in experimental autoimmune encephalomyelitis, an animal model of CNS inflammatory disease. In cultures of brain microvascular endothelial cells, VEGF-A specifically down-regulated CLN-5 and OCLN protein and mRNA. In mouse cerebral cortex, microinjection of VEGF-A disrupted CLN-5 and OCLN and induced loss of barrier function. Importantly, functional studies revealed that expression of recombinant CLN-5 protected brain microvascular endothelial cell cultures from a VEGF-induced increase in paracellular permeability, whereas recombinant OCLN expressed under the same promoter was not protective. Previous studies have shown CLN-5 to be a key determinant of trans-endothelial resistance at the BBB. Our findings suggest that its down-regulation by VEGF-A constitutes a significant mechanism in BBB breakdown.
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Reactive astrocytes are a major source of various vascular permeability factors.
“Reactive astrocytes are a major source of various vascular permeability factors [44–47].”
From Chronic stress-induced depression requires the recruitment of peripheral Th17 cells into the brain (2022) · cites this paper as [45]
The Results (page unavailable) show that reactive astrocytes produce VEGF-A and that medium from stimulated astrocytes increases endothelial permeability, with VEGF-A contributing significantly. The paper establishes this for one permeability factor, but does not establish that reactive astrocytes are a major source of various such factors. (LLM, conf=0.86)
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- Authors
- Argaw, A. T., Gurfein, B. T., Zhang, Y., Zameer, A., & John, G. R.
- Affiliations
- Mount Sinai Hospital (US)
- Albert Einstein College of Medicine (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2009-02-10
- Volume
- 106
- Issue
- 6
- Pages
- 1977-1982
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2644149
- OpenAlex
- W2097573610
- Cited by
- 666
- References
- 41
- Citations by year
- 2026: 39 · 2025: 41 · 2024: 41 · 2023: 40 · 2022: 55 · 2021: 57 · 2020: 51 · 2019: 40 · 2018: 45 · 2017: 38 · 2016: 37 · 2015: 32 · 2014: 30 · 2013: 28 · 2012: 29
- FWCI
- 19.59
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Multiple Sclerosis Society
- Beker Foundation
- National Institutes of Health
- U.S. Public Health Service
- National Cancer Institute (R24CA095823)
- National Institute of Neurological Disorders and Stroke (R01NS062703, R01NS046620, NS056074, R01NS056074, NS46620)
- Topics
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
- Keywords
- VEGF-A, claudin-5, occludin, blood-brain barrier disruption, tight junction proteins, brain microvascular endothelial cells, experimental autoimmune encephalomyelitis, neuroinflammation, paracellular permeability
- MeSH terms
- Animals, Blood-Brain Barrier, Cattle, Cell Membrane Permeability, Cells, Cultured, Central Nervous System, Cerebral Cortex, Disease Models, Animal, Encephalomyelitis, Autoimmune, Experimental, Endothelium, Vascular, Humans, Inflammation, Membrane Proteins, Down-Regulation, Vascular Endothelial Growth Factor A, Mice, Lysosomal Membrane Proteins, Occludin
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