软脑膜侧支是缺血性卒中中免疫响应的血管龛
该研究使用GFP骨髓嵌合小鼠和诱导型单核细胞特异性基因敲除小鼠，经永久性大脑中动脉闭塞模型评估单核细胞募集、侧支重塑、脑血流、梗死体积和功能恢复。结果显示EphA4敲除或单核细胞特异性EphA4缺失可增强侧支扩大、改善灌注并减少梗死。急性大血管闭塞患者血清sTie2水平升高，且与DSA侧支评分改善相关。
要点
- EphA4/Tie2信号是调控软脑膜侧支扩大的关键机制。
- 骨髓来源单核细胞在侧支重塑中发挥核心作用。
- 血清sTie2水平与患者侧支代偿等级相关。
核心结论
- 免疫细胞内在的EphA4/Tie2信号是软脑膜侧支扩大的关键调控因子。
- 靶向EphA4/Tie2轴是增强卒中后灌注的潜在治疗方向。
研究设计与样本
- 使用GFP阳性骨髓嵌合小鼠和诱导型单核细胞特异性Ccr2-CreERT2/EphA4f/f及Ccr2-CreERT2/EphA4f/f/Tie2f/f小鼠。
- 采用永久性大脑中动脉闭塞模型评估单核细胞募集、侧支重塑、脑血流、梗死体积和功能恢复。
- 在急性大血管闭塞患者中分析血清sTie2水平和免疫转录组谱，并与血管造影侧支分级进行相关性分析。
主要发现
- 永久性大脑中动脉闭塞后表达EphA4的单核细胞被快速募集至软脑膜侧支血管。
- EphA4敲除嵌合小鼠显示单核细胞募集显著增加、侧支直径增大、脑血流改善、梗死体积减少和运动恢复加速。
- EphA4缺失的巨噬细胞表现出Tie2、p-Akt和PI3Kα升高，该表型可被PI3Kα抑制或sTie2逆转。
- Ccr2-CreERT2/EphA4f/f小鼠显示侧支扩大增强、神经保护作用和单核细胞募集增强。
- Ccr2-CreERT2/EphA4f/f/Tie2f/f双敲除小鼠中上述增强效应被削弱。
临床怎么用
- 血清sTie2水平可作为大血管闭塞患者侧支代偿状态的潜在生物标志物。
- EphA4/Tie2轴可能成为增强卒中后软脑膜侧支灌注的治疗靶点。
以上解读依据论文摘要（全文未开放获取或许可不允许翻译转载）。
原文
Stroke, Volume 57, Issue 10, Page 3134-3151, October 1, 2026. BACKGROUND:Leptomeningeal collaterals form a critical vascular network that enlarges to support retrograde reperfusion after ischemic stroke, yet the cellular mechanisms governing their structural plasticity remain poorly defined. Here we identify an immune-responsive vascular niche and uncover a central role for bone marrow–derived monocytes in regulating collateral remodeling.METHODS:GFP (green fluorescent protein)+bone marrow chimeric mice and inducible monocyte-specificCcr2-CreERT2(C-C chemokine receptor 2 promoter-driven tamoxifen-inducible Cre recombinase–estrogen receptor T2)/EphA4f/fandCcr2-CreERT2/EphA4f/f/Tie2f/f(tyrosine kinase with immunoglobulin-like and EGF-like domains 2) mice underwent permanent middle cerebral artery occlusion to assess monocyte recruitment, collateral remodeling, cerebral blood flow, infarct volume, and functional recovery. Mechanistic studies evaluated EphA4 (ephrin receptor A4)/Tie2-PI3K (phosphatidylinositol 3-kinase) α signaling in macrophages, while serum sTie2 (soluble Tie2) levels and immune transcriptomic profiles were analyzed in patients with acute large vessel occlusion and correlated with angiographic collateral grade.RESULTS:We observed rapid recruitment of EphA4-expressing monocytes to pial collateral vessels after permanent middle cerebral artery occlusion. EphA4 knockout chimeric mice show a marked increase in monocyte recruitment, enhanced collateral diameters, improved cerebral blood flow, reduced infarct volume, and accelerated motor recovery. EphA4-null macrophages exhibited elevated Tie2, p-Akt (phosphorylated protein kinase B), and PI3Kα, a phenotype reversed by PI3Kα inhibition or sTie2. We further show enhanced permanent middle cerebral artery occlusion–induced collateral enlargement, neuroprotection, and monocyte recruitment usingCcr2-CreERT2/EphA4f/fmice, which is attenuated inCcr2-CreERT2/EphA4f/f/Tie2f/fdouble-knockout mice. Notably, we find that serum sTie2 levels are elevated in human patients with large vessel occlusion, and these levels correlate with improved digital subtraction angiography collateral scoring and key immune-specific bulk transcriptomic changes.CONCLUSIONS:Together, these findings establish immune cell–intrinsic EphA4/Tie2 signaling as a key regulator of leptomeningeal collateral enlargement and reveal a therapeutic axis for augmenting perfusion after stroke.
引用
- Stroke：Leptomeningeal Collaterals Constitute an Immune-Responsive Vascular Niche in Ischemic Stroke
供执业医师工作参考，不替代临床判断；数值与分级以指南原文为准。