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

Research output: Contribution to journalArticlepeer-review

354 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2454-2468
Number of pages15
JournalJournal of Clinical Investigation
Volume122
Issue number7
DOIs
StatePublished - Jul 2 2012

All Science Journal Classification (ASJC) codes

  • Medicine(all)

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