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

Masafumi Hiramatsu, Tomohito Hishikawa, Koji Tokunaga, Hiroyasu Kidoya, Shingo Nishihiro, Jun Haruma, Tomohisa Shimizu, Yuji Takasugi, Yukei Shinji, Kenji Sugiu, Nobuyuki Takakura, Isao Date

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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.

Original languageEnglish
Pages (from-to)679-686
Number of pages8
JournalJournal of Neurosurgery
Issue number3
Publication statusPublished - Sep 1 2017



  • Apelin
  • Gene therapy
  • Moyamoya disease
  • Revascularization
  • Vascular endothelial growth factor

ASJC Scopus subject areas

  • Surgery
  • Medicine(all)
  • Clinical Neurology

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