Astrocyte-derived VEGF-A drives blood-brain barrier disruption in CNS inflammatory disease
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
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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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 8

Reduced clinical severity and neuropathology of EAE in cavtratin-treated mice.

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Reduced clinical severity and neuropathology of EAE in cavtratin-treated...
Mice (8-week-old male C57BL/6, 10 per group) were sensitized with MOG35–55/CFA, then from onset of weight loss (7 dpi) treated for 7 days with 2.5 mg/kg/d i.p. cavtratin or vehicle. (A and B) Disease was scored using a 5-point paradigm (35) and plotted (A) as a function of time and (B) by peak score. (C) Lumbar spinal cord sections were subjected to immunostaining at 21 dpi to assess BBB breakdown (top) as well as demyelination and oligodendrocyte loss (bottom). (D–F) Morphometry of (D) fibrinogen (a measure of BBB breakdown) and CLN-5, (E) CD45 (a measure of inflammatory cell infiltration), and (F) Olig2 and demyelination (assessed by fluoromyelin). These findings resembled the phenotype of EAE in GfapCre:Vegfafl/fl mice (see Figure 5). Scale bars: 50 μm (C, top); 150 μm (C, bottom); 40 μm (C, insets). *P < 0.05, **P < 0.01, ***P < 0.001, ANOVA plus Bonferroni test (A) or Student’s t test (B and D–F). Data are representative of 3 independent experiments.