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Astrocyte-derived VEGF-A drives blood-brain barrier disruption in CNS inflammatory disease
Azeb Tadesse Argaw, … , Michael V. Sofroniew, Gareth R. John
Azeb Tadesse Argaw, … , Michael V. Sofroniew, Gareth R. John
Published June 1, 2012
Citation Information: J Clin Invest. 2012;122(7):2454-2468. https://doi.org/10.1172/JCI60842.
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Research Article Neuroscience Article has an altmetric score of 9

Astrocyte-derived VEGF-A drives blood-brain barrier disruption in CNS inflammatory disease

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Abstract

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.

Authors

Azeb Tadesse Argaw, Linnea Asp, Jingya Zhang, Kristina Navrazhina, Trinh Pham, John N. Mariani, Sean Mahase, Dipankar J. Dutta, Jeremy Seto, Elisabeth G. Kramer, Napoleone Ferrara, Michael V. Sofroniew, Gareth R. John

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Figure 2

GfapCre:Vegfafl/fl animals display reduced BBB breakdown.

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GfapCre:Vegfafl/fl animals display reduced BBB breakdown.
 
(A) 3-dimen...
(A) 3-dimensionally rendered projection from cortex of a 12-week-old C57BL/6 mouse, illustrating intimate association of GFAP+ astrocytic endfeet with CLN-5+ endothelium. (B) Cortical section from the same mouse immunostained for VEGFR2, demonstrating localization to endothelium. (C–E) MVEC cultures from mouse cortex (C and E) and spinal cord (D) were treated with vehicle or 10 ng/ml VEGF-A and harvested at 24 hours, followed by immunostaining (C and D) and immunoblotting (E). Results are typical of data from 3 separate cultures. (F–I) AdIL-1–injected cerebral cortices from 12-week-old GfapCre:Vegfafl/fl mice and littermates sacrificed at 7 dpi (n = 21, at least 4 per genotype, as in Figure 1). (F and G) Immunostaining for CLN-5 (F) and OCLN (G). Individual channels from sections of the merged images are shown below, enlarged 1.5-fold. (H) Morphometry of OCLN and CLN-5. (I) Morphometry of albumin and fibrinogen extravasation (measures of BBB breakdown). Data are representative of 3 independent experiments. Scale bars: 20 μm (A and C); 40 μm (B); 10 μm (D); 50 μm (F and G). *P < 0.05, **P < 0.01, ***P < 0.001, ANOVA plus Bonferroni test.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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