title: AAV-mediated netrin-1 overexpression increases peri-infarct blood vessel density and improves motor function recovery after experimental stroke.
abstract: Apart from its role in axon guidance, netrin-1 is also known to be pro-angiogenic. The aim of this study is to determine whether adeno-associated viral (AAV) mediated overexpression of netrin-1 improves post-stroke neurovascular structure and recovery of function. AAV-Netrin-1 or AAV-LacZ of 1×10(10) genome copies each was injected medial and posterior to ischemic lesion at one hour following reperfusion using the distal middle cerebral artery occlusion (MCAO) method. Quantitative RT-PCR revealed that the expression of netrin-1 transgene began as early as one day and increased dramatically about 3 weeks following vector injection. Western blot analysis and confocal microscopy suggested that both the endogenous and transduced netrin-1 were expressed in the neurons of the peri-infarct cortex after MCAO. AAV-mediated netrin-1 overexpression significantly increased vascular density in the peri-infarct cortex and promoted the migration of immature neurons into the peri-infarct white matter, but it did not significantly reduce infarct size. Netrin-1 overexpression also enhanced post-stroke locomotor activity, improved exploratory behavior, and reduced ischemia-induced motor asymmetry in forelimb usage. However, it had little effect on post-stroke spatial learning and memory. Our results suggest that AAV mediated netrin-1 overexpression improves peri-infarct vascular density and post stroke motor function.
authors: Department of Neurological Surgery, San Francisco, CA, USA.
authors: Hui
authors: H
authors: Sun
authors: Thang
authors: T
authors: Le
authors: Tiffany T J
authors: TT
authors: Chang
authors: Aisha
authors: A
authors: Habib
authors: Steven
authors: S
authors: Wu
authors: Fanxia
authors: F
authors: Shen
authors: William L
authors: WL
authors: Young
authors: Hua
authors: H
authors: Su
authors: Jialing
authors: J
authors: Liu
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D015153:Blotting, Western; D002196:Capillaries / Q000473:pathology; D002465:Cell Movement / Q000235:genetics / Q000502:physiology; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology; D002544:Cerebral Infarction / Q000473:pathology / Q000523:psychology / Q000628:therapy*; D000229:Dependovirus / Q000235:genetics*; D005106:Exploratory Behavior / Q000502:physiology; D019084:Fluorescent Antibody Technique, Indirect; D007839:Functional Laterality / Q000502:physiology; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D007150:Immunohistochemistry; D020244:Infarction, Middle Cerebral Artery / Q000473:pathology / Q000628:therapy; D018782:Maze Learning / Q000502:physiology; D009043:Motor Activity / Q000502:physiology; D009068:Movement / Q000502:physiology*; D018919:Neovascularization, Physiologic / Q000235:genetics*; D009414:Nerve Growth Factors / Q000096:biosynthesis*; D000075388:Netrin-1; D004856:Postural Balance / Q000502:physiology; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020521:Stroke / Q000473:pathology* / Q000523:psychology / Q000628:therapy*; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis*
chemical_list: D009414:Nerve Growth Factors; C000617354:Ntn1 protein, rat; D025521:Tumor Suppressor Proteins; D000075388:Netrin-1