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

Abstract

Astrocyte-derived VEGF-A drives blood-brain barrier disruption in CNS inflammatory disease Azeb Tadesse A r g a w , l ~ ~ , ~ Linnea Asp,1,2g3 Jingya Zhang,132-3 Kristina N a v r a ~ h i n a , ~ , ~ . ~ Trinh Pham,1,2s3 John N. Mariani,1!213 Sean Mahase,l,2z3 Dipankar J. Dutta,lj2,3 Jeremy S e t ~ , l ~ ~ ~ ~ Elisabeth G. Kramer,ls2%3 Napoleone Ferrara,4 Michael V. Sofroniew,s and Gareth R. J0hnl8~9~ ICorinne Goldsmith Dickinson Center for MS, 2Friedman Brain Institute, and 3Department of Neurology, Mount Sinai School of Medicine (MSSM). New York. New York, USA. 4Genentech, Soutli San Francisco, Califor~iia, USA. SDepartment of Neurobiology. David Geffen School of Medicine, UCLA, Los Angeles, California. USA. 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 o f lesion formation that correlates with clinical exacerbation, leading to edema, excitotoxicity, and entry o f serum proteins and inflamlnatory cells. Here, we identify astrocytic expression of VEGF-A as a key driver o f BBB permeability in mice. Inactivation of astrocytic Vedaexpression reduced BBB breakdown, decreased lym- phocyte infiltration and neuropathology in inflammatory and detnyelinating lesions, and reduced paralysis in a mouse model of MS. Knockdown studies in CNS endothelium indicated activation of the downstream effec- tor eNOS as the principal mechanism underlying the effects of VEGF-A on the BBB. Systemic admillistration o f 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 o f VEGF-A signaling as a protective strategy to treat inflammatory CNS disease. Introduction ing MS, VT:.(;F-A is reexprcs.sc.d l'y re.lcriv~ astrocyres , ~ n ~ l it1 s~gnals Tlie blooci-brain barri

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