Semaphorin3A elevates vascular permeability and contributes to cerebral ischemia-induced brain damage

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DOIResolve DOI: http://doi.org/10.1038/srep07890
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TypeArticle
Journal titleScientific Reports
ISSN2045-2322
Volume5
Article number7890
AbstractSemaphorin 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.
Publication date
PublisherNature Publishing Group
LanguageEnglish
AffiliationNational Research Council Canada (NRC-CNRC); Human Health Therapeutics; NRC Institute for Biological Sciences
Peer reviewedYes
NPARC number21277422
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Record identifieraeea0309-c920-41fb-81a7-f791b5dceac9
Record created2016-03-09
Record modified2016-05-09
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