Anti-Vascular Endothelial Growth Factor Treatment Suppresses Early Brain Injury After Subarachnoid Hemorrhage in Mice.
The role of vascular endothelial growth factor (VEGF) in early brain injury (EBI) after subarachnoid hemorrhage (SAH) remains unclear. The aim of this study was to investigate effects of anti-VEGF therapy on EBI after SAH. C57BL/6 male mice underwent sham or filament perforation SAH modeling, and vehicle or two dosages (0.2 and 1 μg) of anti-VEGF antibody were randomly administrated by an intracerebroventricular injection. Neuroscore, brain water content, immunoglobulin G staining, and Western blotting were performed to evaluate EBI at 24-48 h. To confirm the role of VEGF, anti-VEGF receptor (VEGFR)-2 (a major receptor of VEGF) antibody was intracerebroventricularly administered and the effects on EBI were evaluated at 24 h. A higher dose, but not a lower dose, of anti-VEGF antibody significantly ameliorated post-SAH neurological impairments and brain edema at 24-48 h post-SAH. Post-SAH blood-brain barrier disruption was also inhibited by anti-VEGF antibody. The protective effects of anti-VEGF antibody were associated with the inhibition of post-SAH induction of VEGF, VEGFR-2, phosphorylated VEGFR-2, interleukin-1β and a matricellular protein tenascin-C (TNC). Anti-VEGFR-2 antibody also suppressed post-SAH neurological impairments and brain edema associated with VEGFR-2 inactivation and TNC downregulation. These findings demonstrated that VEGF causes post-SAH EBI via VEGFR-2 and TNC and that anti-VEGF therapy is effective for post-SAH EBI.
Department of Neurosurgery, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan.
Lei
L
Liu
Department of Neurosurgery, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan.
Masashi
M
Fujimoto
Department of Neurosurgery, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan.
Fumihiro
F
Kawakita
Department of Neurosurgery, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan.
Fumi
F
Nakano
Department of Pathology and Matrix Biology, Mie University Graduate School of Medicine, Tsu, Japan.|Research Center for Matrix Biology, Mie University Graduate School of Medicine, Tsu, Japan.
Kyoko
K
Imanaka-Yoshida
Department of Pathology and Matrix Biology, Mie University Graduate School of Medicine, Tsu, Japan.|Research Center for Matrix Biology, Mie University Graduate School of Medicine, Tsu, Japan.
Toshimichi
T
Yoshida
Department of Neurosurgery, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan. suzuki02@clin.medic.mie-u.ac.jp.|Research Center for Matrix Biology, Mie University Graduate School of Medicine, Tsu, Japan. suzuki02@clin.medic.mie-u.ac.jp.
Hidenori
H
Suzuki
D000818:Animals; D000906:Antibodies / Q000008:administration & dosage; D001929:Brain Edema / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D001930:Brain Injuries / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011897:Random Allocation; D013345:Subarachnoid Hemorrhage / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors / Q000378:metabolism
D000906:Antibodies; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; C000592875:Kdr protein, mouse; D040301:Vascular Endothelial Growth Factor Receptor-2
Antibody neutralization; Blood-brain barrier; Subarachnoid hemorrhage; Tenascin-C; Vascular endothelial growth factor