Elucidation of the mechanism of rupture of intracranial aneurysm

• Project/Area Number: 20K17929
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 56010:Neurosurgery-related
• Research Institution: Shiga University of Medical Science
• Principal Investigator: Miyata Haruka 滋賀医科大学, 医学部, 客員助教 (40869749)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2022: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2021: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: intracranial aneurysm / rupture / 脳動脈瘤 / 破裂機序 / 慢性炎症 / 動物モデル

Outline of Research at the Start

脳動脈瘤の発生や増大はマクロファージ依存的な慢性炎症により制御されていることはよく知られているが、脳動脈瘤の破裂には脳血管の器質的変化と炎症反応が重要であることが最近の我々の研究から示された (Miyata. J Neurosurg. 2019)。しかしながら、生じうる器質的変化の誘因や破裂に繋がりうる炎症反応の詳細な機構については未解明である。脳動脈瘤が安定した状態を維持する、あるいは破裂に至る変化を生じる機構を解明することは、脳動脈瘤破裂を制御する治療法の開発につながりうる。脳血管壁の器質的変化および破裂と関連する炎症反応の解析を行うことで、脳動脈瘤の破裂を制御する機構を解明する。

Outline of Final Research Achievements

Comprehensive gene expression analysis of the wall of intracranial aneurysms in model animals suggested the involvement of neutrophils in aneurysmal rupture. Spontaneous rupture of intracranial aneurysms was also significantly increased when neutrophil infiltration of the lesion was increased by G-CSF administration to the model animals. In ruptured aneurysm specimens, neutrophil infiltration was predominantly near the vasa vasorum of the wall, and in vivo detection of tissue hypoxia using Hypoxyprobe confirmed the presence of hypoxia in the outer membrane of cerebral aneurysms. Immunostaining showed the expression of FGF2 and VEGF in the same region. We hypothesized that hypoxic stimulation of the aneurysmal adventitia induces FGF2 and VEGF, which in turn induce vasa vasorum growth in the adventitia and rupture of the infiltrated neutrophils.

Academic Significance and Societal Importance of the Research Achievements

脳動脈瘤の破裂機序はこれまでほぼ解明されておらず、未破裂脳動脈瘤に対しての治療介入は外科治療しか選択肢が存在せず、内科治療の創出がunmet medical needとなっている。一方、破裂機序が解明されれば、脳動脈瘤破裂予防に対する薬物治療を創出しうる可能性がある。本研究で明らかになった好中球などの炎症を脳動脈瘤壁局所で制御できれば、脳動脈瘤破裂を予防できる可能性があり、社会的意義があるものと考えられる。

Research Products

• [Journal Article] Involvement of neutrophils in machineries underlying the rupture of intracranial aneurysms (2020)
  • Author(s): Kushamae M, Miyata H, Shirai M, Shimizu K, Oka M, Koseki H, Abekura Y, Ono I, Nozaki K, Mizutani T, Aoki T
  • Journal Title: Scientific Reports Volume: 10 Issue: 1 Pages: 20004-20004
  • DOI: 10.1038/s41598-020-74594-9
  • Peer Reviewed / Open Access
• [Presentation] Neutrophils Infiltrating Through Vasa Vasorum Facilitate Rupture Of Intracranial Aneurysms (2020)
  • Author(s): Mika Kushamae , Tomohiro Aoki , Haruka Miyata , Kazuhiko Nozaki , Tohru Mizutani
  • Organizer: International Stroke Conference 2020
  • Int'l Joint Research