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

被引：568

作者：

Argaw, Azeb Tadesse ^{[1
,2
,3
]}

Asp, Linnea ^{[1
,2
,3
]}

Zhang, Jingya ^{[1
,2
,3
]}

Navrazhina, Kristina ^{[1
,2
,3
]}

Trinh Pham ^{[1
,2
,3
]}

Mariani, John N. ^{[1
,2
,3
]}

Mahase, Sean ^{[1
,2
,3
]}

Dutta, Dipankar J. ^{[1
,2
,3
]}

Seto, Jeremy ^{[1
,2
,3
]}

Kramer, Elisabeth G. ^{[1
,2
,3
]}

Ferrara, Napoleone ^{[4
]}

Sofroniew, Michael V. ^{[5
]}

John, Gareth R. ^{[1
,2
,3
]}

机构：

[1] Mt Sinai Sch Med, Dept Neurol, New York, NY 10029 USA

[2] Mt Sinai Sch Med, Friedman Brain Inst, New York, NY 10029 USA

[3] Mt Sinai Sch Med, Corinne Goldsmith Dickinson Ctr MS, New York, NY 10029 USA

[4] Genentech Inc, San Francisco, CA 94080 USA

[5] Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurobiol, Los Angeles, CA 90095 USA

来源：

JOURNAL OF CLINICAL INVESTIGATION | 2012年 / 122卷 / 07期

关键词：

EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; ENDOTHELIAL GROWTH-FACTOR; CENTRAL-NERVOUS-SYSTEM; NITRIC-OXIDE SYNTHASE; EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS; HUMAN GLIOBLASTOMA-MULTIFORME; MULTIPLE-SCLEROSIS; IN-VIVO; VASCULAR-PERMEABILITY; NEURITE OUTGROWTH;

D O I：

10.1172/JCI60842

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

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.

引用

页码：2454 / 2468

页数：15

共 60 条

[1] The fibrin-derived γ377-395 peptide inhibits microglia activation and suppresses relapsing paralysis in central nervous system autoimmune disease [J].