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 4

Reduced neuropathology in GfapCre:Vegfafl/fl animals.

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Reduced neuropathology in GfapCre:Vegfafl/fl animals. (A–C) AdIL-1–inj...
(A–C) AdIL-1–injected cortices from 12-week-old GfapCre:Vegfafl/fl mice and littermates (7 dpi, n = 3 per genotype) were (A) stained for NeuN (also shown separately) and fibrinogen, and neuronal loss was quantified and plotted (B) per group and (C) against fibrinogen area (a measure of BBB breakdown). (D and E) Cells from A–C were (D) stained for cleaved caspase-3, and (E) the proportion of cleaved caspase-3–positive cells was determined (a measure of apoptosis). (F–I) GfapCre:Vegfafl/fl mice and littermates (12 weeks old, n = 3 per genotype) received a stereotactic microinjection of lysolecithin into the corpus callosum and sacrificed at 7 dpi. (F and G) Immunostaining and quantification for MBP (a measure of demyelination). Arrowheads, extent of demyelination; arrows, injection tracks. (H and I) Staining and morphometry for Olig2 (a marker of oligodendrocyte loss). Scale bars: 150 μm (A and F); 15 μm (D and H). *P < 0.05, ANOVA plus Bonferroni test. Results are representative of data from 3 independent studies.