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

AT Argaw, L Asp, J Zhang… - The Journal of …, 2012 - Am Soc Clin Investig
AT Argaw, L Asp, J Zhang, K Navrazhina, T Pham, JN Mariani, S Mahase, DJ Dutta, J Seto
The Journal of clinical investigation, 2012Am Soc Clin Investig
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 …
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.
The Journal of Clinical Investigation