Astrocyte-derived VEGF-A drives blood-brain barrier disruption in CNS inflammatory disease
Open accessAbstract
In inflammatory CNS conditions such as multiple sclerosis (MS), current options to treat clinical relapse are limited, and more selective agents are needed. Disruption of the blood-brain barrier (BBB) is an early feature of lesion formation that correlates with clinical exacerbation, leading to edema, excitotoxicity, and entry of serum proteins and inflammatory cells. Here, we identify astrocytic expression of VEGF-A as a key driver of BBB permeability in mice. Inactivation of astrocytic Vegfa expression reduced BBB breakdown, decreased lymphocyte infiltration and neuropathology in inflammatory and demyelinating lesions, and reduced paralysis in a mouse model of MS. Knockdown studies in CNS endothelium indicated activation of the downstream effector eNOS as the principal mechanism underlying the effects of VEGF-A on the BBB. Systemic administration of the selective eNOS inhibitor cavtratin in mice abrogated VEGF-A-induced BBB disruption and pathology and protected against neurologic deficit in the MS model system. Collectively, these data identify blockade of VEGF-A signaling as a protective strategy to treat inflammatory CNS disease.
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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 [44]
The Introduction identifies VEGF-A produced by reactive astrocytes as a driver of blood–brain barrier permeability, and the Discussion calls it an important astrocyte-derived inducer of barrier disruption. The paper does not establish that reactive astrocytes are a major source of various vascular permeability factors; its demonstrated finding concerns VEGF-A in CNS inflammatory disease. The indexed passages provide section labels but no page numbers. (LLM, conf=0.84)
Experimental — accuracy not yet measuredVEGF is responsible for multiple important physiological functions, particularly BBB permeability.
“As a pleiotropic growth factor, VEGF is responsible for multiple important physiological functions, particularly BBB permeability [44, 50, 51].”
From Chronic stress-induced depression requires the recruitment of peripheral Th17 cells into the brain (2022) · cites this paper as [44]
The Introduction (p. 2454) identifies VEGF-A as a driver of vessel formation, and the paper reports that astrocyte-derived VEGF-A drives BBB permeability in mice. However, its BBB findings concern disruption during CNS inflammation, not BBB permeability as a normal physiological function; the claim blurs that distinction. (LLM, conf=0.84)
Experimental — accuracy not yet measured
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- Authors
- Argaw, A. T., Asp, L., Zhang, J., Navrazhina, K., Pham, T., Mariani, J. N., Mahase, S., Dutta, D. J., Seto, J., Kramer, E. G., Ferrara, N., Sofroniew, M. V., & John, G. R.
- Affiliations
- Icahn School of Medicine at Mount Sinai (US)
- Genentech (US)
- University of California, Los Angeles (US)
- Corresponding author
- John, Gareth R.
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2012-07-02
- Volume
- 122
- Issue
- 7
- Pages
- 2454-2468
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC3386814
- OpenAlex
- W2170724437
- Cited by
- 733
- References
- 60
- Citations by year
- 2026: 44 · 2025: 64 · 2024: 65 · 2023: 49 · 2022: 73 · 2021: 77 · 2020: 77 · 2019: 39 · 2018: 51 · 2017: 47 · 2016: 36 · 2015: 47 · 2014: 27 · 2013: 32 · 2012: 4
- FWCI
- 17.69
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (RG4127, RG3874)
- U.S. Public Health Service
- National Cancer Institute (R24CA095823)
- National Institute of Allergy and Infectious Diseases (HHSN272201000054C)
- National Institute of Neurological Disorders and Stroke (R01NS062703, R01NS046620, R01NS056074, T32NS051147, R01NS057624)
- Topics
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Keywords
- VEGF-A, astrocytes, blood-brain barrier permeability, multiple sclerosis, neuroinflammation, endothelial nitric oxide synthase, lymphocyte infiltration, demyelination, neuroprotection
- MeSH terms
- Animals, Astrocytes, Blood-Brain Barrier, Brain, Cells, Cultured, Demyelinating Diseases, DNA-Binding Proteins, Gene Expression Regulation, Humans, Inflammation, Lymphocytes, Male, Membrane Glycoproteins, Membrane Proteins, Mice, Inbred C57BL, Mice, Transgenic, Multiple Sclerosis, Nerve Tissue Proteins, Nuclear Proteins, Permeability, Cytokines, Vascular Endothelial Growth Factor Receptor-2, Vascular Endothelial Growth Factor A, Mice, Lysosomal Membrane Proteins, Nitric Oxide Synthase Type III, Interleukin-1beta, Primary Cell Culture, Occludin
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