High-Mobility Group Box-1-Induced Angiogenesis After Indirect Bypass Surgery in a Chronic Cerebral Hypoperfusion Model

Shingo Nishihiro,Naoya Kidani,Satoshi Murai,Masafumi Hiramatsu,Tomohito Hishikawa,Yu Takahashi,Isao Date,Kenji Sugiu,Takao Yasuhara,Cesario V Borlongan,Yusuke Higaki

doi:10.1007/s12017-019-08541-x

Shingo Nishihiro, Naoya Kidani + Show 9 more

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https://doi.org/10.1007/s12017-019-08541-x

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Abstract

High-mobility group box-1 (HMGB1) is a nuclear protein that promotes inflammation during the acute phase post-stroke, and enhances angiogenesis during the delayed phase. Here, we evaluated whether indirect revascularization surgery with HMGB1 accelerates brain angiogenesis in a chronic cerebral hypoperfusion model. Seven days after hypoperfusion induction, encephalo-myo-synangiosis (EMS) was performed with or without HMGB1 treatment into the temporal muscle. We detected significant increments in cortical vasculature (p < 0.01), vascular endothelial growth factor (VEGF) expression in the temporal muscle (p < 0.05), and ratio of radiation intensity on the operated side compared with the non-operated side after EMS in the HMGB1-treated group than in the control group (p < 0.01). Altogether, HMGB1 with EMS in a chronic hypoperfusion model promoted brain angiogenesis in a VEGF-dependent manner, resulting in cerebral blood flow improvement. This treatment may be an effective therapy for patients with moyamoya disease.

Highlights

Moyamoya disease (MMD) is a chronic cerebral hypoperfusion state that is characterized by progressive stenosis or occlusion of the intracranial internal carotid artery (Kuroda and Houkin 2008)
We previously examined the effect of indirect revascularization surgery with vascular endothelial growth factor (VEGF) gene administration into the temporal muscle in a chronic cerebral hypoperfusion state in a rat model (Kusaka et al 2005; Katsumata et al 2010)
EMS for the hypoperfusion state after bilateral common carotid artery (CCA) ligation simulated indirect bypass surgery for patients with MMD. These results indicate that EMS with combined gene therapy significantly enhanced angiogenesis in the brain cortex compared to EMS alone

Summary

Introduction

Moyamoya disease (MMD) is a chronic cerebral hypoperfusion state that is characterized by progressive stenosis or occlusion of the intracranial internal carotid artery (Kuroda and Houkin 2008). High-mobility group box-1 (HMGB1) is a non-histone nuclear DNA-binding protein that is present in most eukaryotic cells, including neural cells, to stabilize nucleosome formation, and it is related to gene expression such as. NeuroMolecular Medicine (2019) 21:391–400 gene transcription, replication, and DNA repair (van Beijnum et al 2008; Hayakawa et al 2010; Sama et al 2004). We investigated whether EMS combined with HMGB1 administration promotes brain angiogenesis in a chronic cerebral hypoperfusion model in rats. We examined whether brain angiogenesis contributed to improving cerebral perfusion

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