Kaempferol promotes angiogenesis through HIF-1α/VEGF-A/Notch1 pathway in ischemic stroke rats.

IF 4.4 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Neurochemistry international Pub Date : 2025-02-21 DOI:10.1016/j.neuint.2025.105953
Sen Zhang, Chengdi Liu, Wan Li, Yizhi Zhang, Yihui Yang, Hong Yang, Ziyuan Zhao, Fang Xu, Wanxin Cao, Xiaoxue Li, Jinhua Wang, Linglei Kong, Guanhua Du
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Abstract

Stroke is a severe disease characterized by the obstruction of blood vessels in the central nervous system. An essential therapeutic strategy for ischemic stroke is strengthening angiogenesis, which effectively promotes the long-term recovery of neurological function. Therefore, it is critical to explore and develop new drugs that promote angiogenesis after ischemic stroke. Kaempferol has been employed to treat ischemic diseases; However, its proangiogenic effects in ischemic stroke remain unclear. In the study, we explored the long-term therapeutic effects and mechanisms of kaempferol on ischemic stroke in vivo and in vitro. A rat model of autologous thrombus stroke and oxygen-glucose deprivation (OGD)-induced human brain microvascular endothelial cells (HBMECs) model was established to assess the effects of kaempferol in vivo (50 mg/kg/d, ig, 14 d) and in vitro (0.1, 0.3, 1 μmol·L-1). The results showed that long-term administration of kaempferol ameliorated neurological deficits and infarct volume in ischemic stroke rats. In addition, kaempferol relieved vascular embolization; enhanced microvascular endothelial cell survival, proliferation, migration, and lumen formation; increased the density of microvessels in the peri-infarct cortex; and promoted neovascular structure remodeling by increasing the coverage of astrocyte end-feet and expression of tight-junction proteins (TJPs). Further analysis revealed that the HIF-1α/VEGF-A/Notch1 signaling pathway was activated by kaempferol, and that inhibition of Notch1 blocked kaempferol-induced angiogenesis. Taken together, our results indicate that kaempferol exerts neuroprotective effects by stimulating endogenous angiogenesis and neovascular structural remodeling via the HIF-1α/VEGF-A/Notch1 signaling pathway, suggesting the therapeutic potential of kaempferol in ischemic stroke.

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中风是一种以中枢神经系统血管阻塞为特征的严重疾病。缺血性脑卒中的重要治疗策略是加强血管生成,从而有效促进神经功能的长期恢复。因此,探索和开发促进缺血性中风后血管生成的新药至关重要。山奈酚已被用于治疗缺血性疾病,但其在缺血性脑卒中中的促血管生成作用尚不明确。本研究探讨了山奈酚在体内和体外对缺血性中风的长期治疗作用和机制。我们建立了自体血栓脑卒中大鼠模型和氧-葡萄糖剥夺(OGD)诱导的人脑微血管内皮细胞(HBMECs)模型,以评估山奈酚在体内(50 mg/kg/d, ig, 14 d)和体外(0.1, 0.3, 1 μmol-L-1)的作用。结果表明,长期服用山奈酚可改善缺血性脑卒中大鼠的神经功能缺损和梗死体积。此外,山奈酚还能缓解血管栓塞;增强微血管内皮细胞的存活、增殖、迁移和管腔形成;增加梗死周围皮层的微血管密度;通过增加星形胶质细胞端足的覆盖率和紧密连接蛋白(TJPs)的表达,促进新生血管结构的重塑。进一步的分析表明,山奈酚激活了 HIF-1α/VEGF-A/Notch1 信号通路,而抑制 Notch1 则阻断了山奈酚诱导的血管生成。综上所述,我们的研究结果表明,山奈酚通过HIF-1α/VEGF-A/Notch1信号通路刺激内源性血管生成和新生血管结构重塑,从而发挥神经保护作用,提示山奈酚对缺血性脑卒中具有治疗潜力。
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来源期刊
Neurochemistry international
Neurochemistry international 医学-神经科学
CiteScore
8.40
自引率
2.40%
发文量
128
审稿时长
37 days
期刊介绍: Neurochemistry International is devoted to the rapid publication of outstanding original articles and timely reviews in neurochemistry. Manuscripts on a broad range of topics will be considered, including molecular and cellular neurochemistry, neuropharmacology and genetic aspects of CNS function, neuroimmunology, metabolism as well as the neurochemistry of neurological and psychiatric disorders of the CNS.
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