Wolters Kluwer Acta Medica Okayama 2394-8108 5 3 2019 Cerebral circulation improves with indirect bypass surgery combined with gene therapy 119 123 EN Alex Shear Department of Neurosurgery and Brain Repair, College of Medicine, University of South Florida Morsani Shingo Nishihiro Department of Neurological Surgery, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University Tomohito Hishikawa Department of Neurological Surgery, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University Masafumi Hiramatsu Department of Neurological Surgery, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University Kenji Sugiu Department of Neurological Surgery, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University Takao Yasuhara Department of Neurological Surgery, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University Isao Date Department of Neurological Surgery, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University Angiogenesis involves new blood vessels sprouting from preexisting blood vessels. This process may serve to improve brain circulation. Moyamoya disease (MMD) is a cerebrovascular disorder causing intracranial stenosis which significantly reduces the blood supply to the brain. Mainly stroke is the first symptom of the disorder, so treatments that reduce the risk of stroke are used for patients with MMD. To prevent stroke for those with chronic cerebral hypoperfusion, more blood needs to flow to the brain, which was thought to be achieved by enhancing angiogenesis. Indirect bypass surgery, such as encephalo-myo-synangiosis (EMS), is used for revascularization. However, EMS alone sometimes cannot provide enough circulation to avoid ischemic strokes. The current study examined if EMS combined with high-mobility group box-1 (HMGB1) and vascular endothelial growth factor (VEGF) enhanced angiogenesis and increased cerebral circulation. The results indicated that HMGB1 administered with EMS increased angiogenesis through a VEGF-dependent mechanism. In addition, exercising and stem cell transplantation possess possible means to increase angiogenesis. Overall, EMS with gene therapy, maintaining fitness, and stem cell utilization may prevent or help one recover from stroke by enhancing brain angiogenesis. Thus, these treatments may be applicable for patients with MMD. This paper is a review article. Referred literature in this paper has been listed in the references section. The datasets supporting the conclusions of this article are available online by searching various databases, including PubMed. No potential conflict of interest relevant to this article was reported.