中国神经再生研究(英文版) ›› 2026, Vol. 21 ›› Issue (7): 3007-3016.doi: 10.4103/NRR.NRR-D-24-01323

• 原著:脑损伤修复保护与再生 • 上一篇    下一篇

神经调节蛋白1促进缺血性脑卒中后血管生成

  

  • 出版日期:2026-07-15 发布日期:2026-03-27

Macrophages-derived NRG-1 promotes angiogenesis after ischemic stroke via the Akt-mTOR pathway.

Jie Chen1, #, Bo Wang2, #, Danyang Fan1, Xi Chen1, Lenv Gao1, Yun Luo3, *, Zhenhua Zhou1, *   

  1. 1Department of Neurology, The First Affiliated Hospital of Army Medical University, Army Medical University, Chongqing, China; 
    2Department of Neurosurgery, The First Affiliated Hospital of Army Medical University, Army Medical University, Chongqing, China; 
    3Department of Rehabilitation Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi Province, China
  • Online:2026-07-15 Published:2026-03-27
  • Contact: Zhenhua Zhou, MD, exploiter001@126.com; Yun Luo, MD, 735083566@qq.com.
  • Supported by:
    This work was supported by the Chongqing Technology lnnovation and Application Development Program, No. CSTB2023TIAD-KPX0061 (to ZZ); the National Natural Science Foundation of China, Nos. 81971130 (to ZZ) and 82201464 (to XC).

摘要:

近年来,神经调节蛋白1在脑缺血中表现出了良好的神经保护作用,但其作用机制尚在研究中。实验收集了急性脑梗死患者的血块和配对外周血样本,以分析神经调节蛋白1的来源。此外,还建立了大脑中动脉阻塞小鼠模型,研究神经调节蛋白1对大脑中动脉阻塞小鼠的治疗效果及其潜在的分子生物学机制。结果显示,急性脑梗死患者血清中的神经调节蛋白1水平明显升高,与神经功能损伤的严重程度和临床预后相关。通过单细胞测序,在外周血单核细胞中发现了神经调节蛋白1阳性的巨噬细胞,这些巨噬细胞在缺血后会产生神经调节蛋白1。此外,神经调节蛋白1在促进梗死区域的修复、减轻神经元和髓鞘损伤以及改善小鼠整体行为恢复方面具有潜力。神经调节蛋白1可通过梗死区域的血管生成发挥这些神经保护作用,而这种血管生成促进作用是由 Akt/mTOR/VEGF 依赖性信号通路介导的。结果表明,外周来源的巨噬细胞是脑卒中后神经调节蛋白1的来源。神经调节蛋白1通过Akt/mTOR/VEGF依赖性信号通路促进缺血性脑卒中后血管生成,从而发挥神经保护作用,具有广阔的临床应用前景。

https://orcid.org/0000-0002-4548-4489 (Zhenhua Zhou); 

https://orcid.org/0000-0002-9928-1898 (Yun Luo)

关键词: 急性缺血性脑卒中, 血管生成, 血栓, ErbB4, 荧光激活细胞分拣, 免疫细胞, 炎症, 巨噬细胞, 神经保护, 神经调节蛋白1

Abstract: Acute ischemic stroke remains a significant health concern owing to the limited efficacy of current therapeutic options. In recent years, Neuregulin-1 has exhibited promising neuroprotective effects in cerebral ischemia. However, the sources and functions of Neuregulin-1 have not yet been fully understood, which hinders its translation and broad application. Here, we collected paired clot and peripheral blood samples from patients with acute ischemic stroke to determine the sources of Neuregulin-1. In addition, we established an in vivo transient middle cerebral artery occlusion mouse model to investigate the therapeutic effects of Neuregulin-1 and its underlying molecular biological mechanisms. We observed a significant elevation in serum Neuregulin-1 levels among patients with acute ischemic stroke that correlated with severity of neurological impairment and clinical outcome. Using single-cell sequencing, we identified Neuregulin-1-positive macrophages among peripheral blood mononuclear cells that produced Neuregulin-1 postischemia. In addition, Neuregulin-1 promoted repair of the infarcted area, alleviating neuronal and myelin damage and improving overall behavioral recovery in mice. We found that Neuregulin-1 may exert these neuroprotective effects by promoting angiogenesis in the infarct area, and that this effect is mediated by Akt/mTOR/VEGF-dependent signaling. Our findings suggest that peripheral macrophages are a source of Neuregulin-1 post-stroke. Neuregulin-1 exerts its neuroprotective effects by promoting angiogenesis via Akt/mTOR/VEGF-dependent signaling, showing promising clinical translation potential.

Key words: acute ischemic stroke, angiogenesis, Clot, ErbB4, fluorescence-activated cell sorting, immune cell, inflammation, macrophages, Neuregulin-1, neuroprotection