雷帕霉素治疗减少缺血性脑卒中中的脑微血管周细胞收缩
Rapamycin Treatment Reduces Brain Pericyte Constriction in Ischemic Stroke
影响因子:4.30000
分区:医学2区 / 临床神经病学2区 神经科学2区
发表日期:2025 Aug
作者:
Daniel J Beard, Lachlan S Brown, Gary P Morris, Yvonne Couch, Bryan A Adriaanse, Christina Simoglou Karali, Anna M Schneider, David W Howells, Zoran B Redzic, Brad A Sutherland, Alastair M Buchan
摘要
脑微血管周细胞的收缩及其随后的死亡可能在血管再通后微血管血流恢复障碍中发挥作用。哺乳动物雷帕霉素靶蛋白（mTOR）抑制已被证明可以减少多种癌细胞系的运动性/收缩性以及降低卒中中的神经元细胞死亡。然而，mTOR抑制对缺血期间脑微血管周细胞收缩和死亡的影响尚未被研究。在体外模拟缺血12小时的培养微血管周细胞在不到1小时内收缩，早于细胞死亡约7小时。雷帕霉素显著减缓了缺血期间微血管周细胞的收缩速度，但在任何时间点都未明显影响其存活。雷帕霉素似乎通过一种与细胞内钙离子变化无关的机制减弱微血管周细胞的收缩。利用小鼠中脑动脉阻塞模型，我们发现雷帕霉素显著增加微血管周细胞下方毛细血管的直径，并在再血管化后30分钟内增加开放毛细血管的数量。我们的发现提示，雷帕霉素可能作为一种有用的辅助治疗药物，用于减少微血管周细胞收缩并改善卒中后的脑血流再灌注。
Abstract
The contraction and subsequent death of brain pericytes may play a role in microvascular no-reflow following the reopening of an occluded artery during ischemic stroke. Mammalian target of rapamycin (mTOR) inhibition has been shown to reduce motility/contractility of various cancer cell lines and reduce neuronal cell death in stroke. However, the effects of mTOR inhibition on brain pericyte contraction and death during ischemia have not yet been investigated. Cultured pericytes exposed to simulated ischemia for 12 h in vitro contracted after less than 1 h, which was about 7 h prior to cell death. Rapamycin significantly reduced the rate of pericyte contraction during ischemia; however, it did not have a significant effect on pericyte viability at any time point. Rapamycin appeared to reduce pericyte contraction through a mechanism that is independent of changes in intracellular calcium. Using a mouse model of middle cerebral artery occlusion, we showed that rapamycin significantly increased the diameter of capillaries underneath pericytes and increased the number of open capillaries 30 min following recanalisation. Our findings suggest that rapamycin may be a useful adjuvant therapeutic to reduce pericyte contraction and improve cerebral reperfusion post-stroke.