Title | Astrocyte-derived VEGF-A drives blood-brain barrier disruption in CNS inflammatory disease. |
Publication Type | Journal Article |
Year of Publication | 2012 |
Authors | Argaw ATadesse, Asp L, Zhang J, Navrazhina K, Pham T, Mariani JN, Mahase S, Dutta DJ, Seto J, Kramer EG, Ferrara N, Sofroniew MV, John GR |
Journal | J Clin Invest |
Volume | 122 |
Issue | 7 |
Pagination | 2454-68 |
Date Published | 2012 Jul |
ISSN | 1558-8238 |
Keywords | Animals, Astrocytes, Blood-Brain Barrier, Brain, Cells, Cultured, Cytokines, Demyelinating Diseases, DNA-Binding Proteins, Gene Expression Regulation, Humans, Inflammation, Interleukin-1beta, Lymphocytes, Male, Membrane Glycoproteins, Membrane Proteins, Mice, Mice, Inbred C57BL, Mice, Transgenic, Multiple Sclerosis, Nerve Tissue Proteins, Nitric Oxide Synthase Type III, Nuclear Proteins, Occludin, Permeability, Primary Cell Culture, Vascular Endothelial Growth Factor A, Vascular Endothelial Growth Factor Receptor-2 |
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. |
DOI | 10.1172/JCI60842 |
Alternate Journal | J. Clin. Invest. |
PubMed ID | 22653056 |
PubMed Central ID | PMC3386814 |
Grant List | T32 NS051147 / NS / NINDS NIH HHS / United States R01NS056074 / NS / NINDS NIH HHS / United States HHSN272201000054C / AI / NIAID NIH HHS / United States T32NS051147-03 / NS / NINDS NIH HHS / United States RG4127 / RG / CSR NIH HHS / United States R01 NS056074 / NS / NINDS NIH HHS / United States R01 NS057624 / NS / NINDS NIH HHS / United States R01 NS046620 / NS / NINDS NIH HHS / United States RG3874 / RG / CSR NIH HHS / United States R01NS057624 / NS / NINDS NIH HHS / United States R24 CA095823 / CA / NCI NIH HHS / United States R01NS046620 / NS / NINDS NIH HHS / United States R24CA095823 / CA / NCI NIH HHS / United States R01 NS062703 / NS / NINDS NIH HHS / United States R01NS062703 / NS / NINDS NIH HHS / United States |
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