title: Semaphorin3A elevates vascular permeability and contributes to cerebral ischemia-induced brain damage.
abstract: Semaphorin 3A (Sema3A) increased significantly in mouse brain following cerebral ischemia. However, the role of Sema3A in stroke brain remains unknown. Our aim was to determine wether Sema3A functions as a vascular permeability factor and contributes to ischemic brain damage. Recombinant Sema3A injected intradermally to mouse skin, or stereotactically into the cerebral cortex, caused dose- and time-dependent increases in vascular permeability, with a degree comparable to that caused by injection of a known vascular permeability factor vascular endothelial growth factor receptors (VEGF). Application of Sema3A to cultured endothelial cells caused disorganization of F-actin stress fibre bundles and increased endothelial monolayer permeability, confirming Sema3A as a permeability factor. Sema3A-mediated F-actin changes in endothelial cells were through binding to the neuropilin2/VEGFR1 receptor complex, which in turn directly activates Mical2, a F-actin modulator. Down-regulation of Mical2, using specific siRNA, alleviated Sema3A-induced F-actin disorganization, cellular morphology changes and endothelial permeability. Importantly, ablation of Sema3A expression, cerebrovascular permeability and brain damage were significantly reduced in response to transient middle cerebral artery occlusion (tMCAO) and in a mouse model of cerebral ischemia/haemorrhagic transformation. Together, these studies demonstrated that Sema3A is a key mediator of cerebrovascular permeability and contributes to brain damage caused by cerebral ischemia.
authors.affiliation: 1] Department of Biology, South University of Science and Technology of China, 1088 Xueyuan Blvd, Nanshan District, Shenzhen, P.R. China, 518055 [2] Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada [3] Human Health Therapeutics Portfolio, National Research Council Canada, 1200 Montreal Road, Bldg M54, Ottawa, Ontario, K1A 0R6, Canada.
authors.forename: Sheng Tao
authors.initials: ST
authors.lastname: Hou
authors.affiliation: 1] Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada [2] Human Health Therapeutics Portfolio, National Research Council Canada, 1200 Montreal Road, Bldg M54, Ottawa, Ontario, K1A 0R6, Canada.
authors.forename: Ladan
authors.initials: L
authors.lastname: Nilchi
authors.affiliation: 1] Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada [2] Human Health Therapeutics Portfolio, National Research Council Canada, 1200 Montreal Road, Bldg M54, Ottawa, Ontario, K1A 0R6, Canada.
authors.forename: Xuesheng
authors.initials: X
authors.lastname: Li
authors.affiliation: Human Health Therapeutics Portfolio, National Research Council Canada, 1200 Montreal Road, Bldg M54, Ottawa, Ontario, K1A 0R6, Canada.
authors.forename: Sandhya
authors.initials: S
authors.lastname: Gangaraju
authors.affiliation: Human Health Therapeutics Portfolio, National Research Council Canada, 1200 Montreal Road, Bldg M54, Ottawa, Ontario, K1A 0R6, Canada.
authors.forename: Susan X
authors.initials: SX
authors.lastname: Jiang
authors.affiliation: Human Health Therapeutics Portfolio, National Research Council Canada, 1200 Montreal Road, Bldg M54, Ottawa, Ontario, K1A 0R6, Canada.
authors.forename: Amy
authors.initials: A
authors.lastname: Aylsworth
authors.affiliation: Human Health Therapeutics Portfolio, National Research Council Canada, 1200 Montreal Road, Bldg M54, Ottawa, Ontario, K1A 0R6, Canada.
authors.forename: Robert
authors.initials: R
authors.lastname: Monette
authors.affiliation: Human Health Therapeutics Portfolio, National Research Council Canada, 1200 Montreal Road, Bldg M54, Ottawa, Ontario, K1A 0R6, Canada.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Slinn
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001930:Brain Injuries / Q000235:genetics* / Q000503:physiopathology; D002545:Brain Ischemia / Q000235:genetics / Q000503:physiopathology; D002199:Capillary Permeability / Q000235:genetics* / Q000502:physiology; D002540:Cerebral Cortex / Q000293:injuries / Q000473:pathology; D003598:Cytoskeletal Proteins / Q000096:biosynthesis; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D008840:Microfilament Proteins; D039943:Neuropilin-2 / Q000378:metabolism; D040121:Semaphorin-3A / Q000008:administration & dosage / Q000235:genetics*; D020521:Stroke / Q000235:genetics* / Q000503:physiopathology; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics / Q000378:metabolism
chemical_list: D000199:Actins; D003598:Cytoskeletal Proteins; C512298:JRAB protein, mouse; D008840:Microfilament Proteins; D039943:Neuropilin-2; C488217:Sema3a protein, mouse; D040121:Semaphorin-3A; D040281:Vascular Endothelial Growth Factor Receptor-1