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

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

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 1

Efficient inactivation of VEGF-A in the inflamed CNS in GfapCre:Vegfafl/fl mice.

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Efficient inactivation of VEGF-A in the inflamed CNS in GfapCre:Vegfafl/...
(A) Mice with loxP sites flanking Vegfa exon 3 were bred with an mGfapCre line. (B) Final matings generated GfapCre:Vegfafl/fl mice and GfapCre:Vegfa+/fl, Vegfafl/fl, and Vegfa+/fl controls, with experimental pups representing 25% of total. (C and D) Immunoreactivity for the endothelial protein F8R and BBB junction components CLN-5 and OCLN in cerebral cortices of 12-week-old GfapCre:Vegfafl/fl mice and littermates (n = 3 per genotype). (E) ELISA of primary human astrocytes showing VEGF-A induction by vehicle or 10 ng/ml IL-1β, TGF-β1, or IFN-γ at 24 hours. Results are typical of cultures from 3 separate brains. (F and G) AdIL-1 (107 pfu) was microinjected into cortical gray matter of 12-week-old GfapCre:Vegfafl/fl mice and littermates (n = 21, at least 4 per genotype); animals were sacrificed at 7 dpi, based on time course studies (see Supplemental Figures 1 and 2); and lesions were stained and examined to determine the number of GFAP+ and VEGF-A+ cells. Data are representative of 3 independent experiments. In G, individual channels from sections of the merged images are shown at right. See Supplemental Figure 1D for higher-magnification images of VEGF-A+GFAP+ cells. Scale bars: 50 μm (C and G). *P < 0.05, **P < 0.01, ***P < 0.001, ANOVA plus Bonferroni test.