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J Neurosurg. 2017 Sep;127(3):679-686. doi: 10.3171/2016.8.JNS16366. Epub 2016 Dec 23.

Combined gene therapy with vascular endothelial growth factor plus apelin in a chronic cerebral hypoperfusion model in rats.

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Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences.
Department of Neurosurgery, Okayama City Hospital, Okayama; and.
Department of Signal Transduction, Research Institute for Microbial Diseases, Osaka University, Suita, Japan.


OBJECTIVE The aim of this study was to evaluate whether combined gene therapy with vascular endothelial growth factor (VEGF) plus apelin during indirect vasoreconstructive surgery enhances brain angiogenesis in a chronic cerebral hypoperfusion model in rats. METHODS A chronic cerebral hypoperfusion model induced by the permanent ligation of bilateral common carotid arteries (CCAs; a procedure herein referred to as "CCA occlusion" [CCAO]) in rats was employed in this study. Seven days after the CCAO procedure, the authors performed encephalo-myo-synangiosis (EMS) and injected plasmid(s) into each rat's temporal muscle. Rats were divided into 4 groups based on which plasmid was received (i.e., LacZ group, VEGF group, apelin group, and VEGF+apelin group). Protein levels in the cortex and attached muscle were assessed with enzyme-linked immunosorbent assay (ELISA) on Day 7 after EMS, while immunofluorescent analysis of cortical vessels was performed on Day 14 after EMS. RESULTS The total number of blood vessels in the cortex on Day 14 after EMS was significantly larger in the VEGF group and the VEGF+apelin group than in the LacZ group (p < 0.05, respectively). Larger vessels appeared in the VEGF+apelin group than in the other groups (p < 0.05, respectively). Apelin protein on Day 7 after EMS was not detected in the cortex for any of the groups. In the attached muscle, apelin protein was detected only in the apelin group and the VEGF+apelin group. Immunofluorescent analysis revealed that apelin and its receptor, APJ, were expressed on endothelial cells (ECs) 7 days after the CCAO. CONCLUSIONS Combined gene therapy (VEGF plus apelin) during EMS in a chronic cerebral hypoperfusion model can enhance angiogenesis in rats. This treatment has the potential to be a feasible option in a clinical setting for patients with moyamoya disease.


Ang-1 = angiopoietin-1; CBF = cerebral blood flow; CCA = common carotid artery; CCAO = CCA occlusion; EC = endothelial cells; ELISA = enzyme-linked immunosorbent assay; EMS = encephalo-myo-synangiosis; MMD = moyamoya disease; PBS = phosphate-buffered saline; PFA = paraformaldehyde; RECA-1 = mouse monoclonal anti-EC antibody; VEGF = vascular endothelial growth factor; apelin; gene therapy; moyamoya disease; revascularization; vascular endothelial growth factor


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