Astrocyte-derived VEGF-A drives blood-brain barrier disruption in CNS inflammatory disease.
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.
Corinne Goldsmith Dickinson Center for MS, New York, NY, USA.
Azeb Tadesse
AT
Argaw
Linnea
L
Asp
Jingya
J
Zhang
Kristina
K
Navrazhina
Trinh
T
Pham
John N
JN
Mariani
Sean
S
Mahase
Dipankar J
DJ
Dutta
Jeremy
J
Seto
Elisabeth G
EG
Kramer
Napoleone
N
Ferrara
Michael V
MV
Sofroniew
Gareth R
GR
John
D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D001812:Blood-Brain Barrier / Q000378:metabolism* / Q000473:pathology; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004268:DNA-Binding Proteins; D003711:Demyelinating Diseases; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D053583:Interleukin-1beta / Q000502:physiology; D008214:Lymphocytes / Q000473:pathology; D051907:Lysosomal Membrane Proteins; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009103:Multiple Sclerosis / Q000378:metabolism* / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D062793:Occludin; D010539:Permeability; D061251:Primary Cell Culture; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
C488572:Cln5 protein, mouse; D016207:Cytokines; D004268:DNA-Binding Proteins; D053583:Interleukin-1beta; D051907:Lysosomal Membrane Proteins; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C492380:NeuN protein, mouse; D009687:Nuclear Proteins; C568985:OCLN protein, human; D062793:Occludin; C568986:Ocln protein, mouse; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D040301:Vascular Endothelial Growth Factor Receptor-2