S1P1 activation enhances leptomeningeal collateral development and improves outcome after stroke

2019 Fiscal Year Final Research Report

• Project/Area Number: 17K10820
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurosurgery
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: MIki Kazunori 東京医科歯科大学, 大学院医歯学総合研究科, 助教 (00536823)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: 脳動脈新生 / 側副血行 / 脳血管障害 / スフィンゴシン1-リン酸受容体 / 齧歯類モデル

Outline of Final Research Achievements

Collateral development after acute ischemic stroke is triggered by shear stress, and sphingosine-1-phosphate receptor 1 (S1P1) on endothelial cells was reported to sense shear stress and transduce its signalling pathways. We investigated the effect of an S1P1-selective agonist (SEW2871) on leptomeningeal collateral arteries in acute stroke model.
Nneurological functions, leptomeningeal arteries, and infarct volume were compared after treatment. S1P1 expression in endothelial cells was increased after pMCAO. The number of leptomeningeal collateral arteries was significantly increased and neurological outcome improved. Endothelial nitric oxide synthase (eNOS) phosphorylation and the expression of tight junction proteins was increased in the SEW2871 group.
S1P1-selective agonist enhanced leptomeningeal collateral circulation via eNOS phosphorylation and reinforced BBB integrity in acute ischemic stroke mice, leading to smaller infarct volume and better neurological outcome.

Free Research Field

脳血管障害

Academic Significance and Societal Importance of the Research Achievements

脳梗塞治療として再開通療法と同時に、脳血流の低下を防ぎ、いかに梗塞に陥らせないかという治療戦略が非常に重要であり、実現すれば非常に多くの脳梗塞症例に適応しうる。実際に成体脳であっても脳梗塞後に新たな血管が形成される現象が認められ、特に血管内皮細胞だけでなく平滑筋、基底膜よりなる口径の大きな新たな機能する動脈の発達を意味するArteriogenesis（動脈新生）は、脳の主幹動脈が閉塞した場合に側副血行路として機能し、脳血流の保持が可能となる。今回脳梗塞齧歯類モデルにおいて、脳表の動脈新生の発達した症例では脳梗塞の梗塞体積が減少し、機能予後が良好であること確認した。