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 3

Reduced lymphocyte infiltration in GfapCre:Vegfafl/fl mice.

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Reduced lymphocyte infiltration in GfapCre:Vegfafl/fl mice. (A–G) AdIL...
(A–G) AdIL-1–microinjected cortices were harvested at 7 dpi from 12-week-old GfapCre:Vegfafl/fl mice and littermates (at least 4 per genotype, n = 21). Shown are immunostaining and morphometry of (A and B) CD11b, (B and C) CD4, (C) CD19, (D and E) VCAM-1 and CXCL12, and (F and G) MMP-9 and MMP-3. Data are representative of findings from 3 independent experiments. (H and I) Human CNS MVECs were treated with 10 ng/ml IL-1β or 10 or 100 ng/ml VEGF-A for 24 hours, and (H) expression of VCAM-1 and ICAM-1 were determined by immunoblotting, and (I) concentrations of CC and CXC chemokines and cytokines were quantified. Data are representative of 3 experiments in separate cultures. (J and K) 12-week-old C57BL/6 mice (n = 4 per group) received 50 mg/ml MP or vehicle i.p., then intracerebral microinjection of AdIL-1 24 hours later, and were sacrificed at 7 dpi and examined to determine (J) the proportion of GFAP+, VEGF-A+, and CD4+ cells (measures of immunoreactivity and lymphocyte infiltration) and (K) the expression of fibrinogen and VCAM (measures of BBB breakdown). Data are representative of findings from 3 independent experiments. Scale bars: 50 μm (A, C, E, G, and all insets). *P < 0.05, **P < 0.01, ***P < 0.001, ANOVA plus Bonferroni test (B, D, F, and I) or Student’s t test (J and K).