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

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

  • Neurochem Int. 2025 Feb 21:185:105953. doi: 10.1016/j.neuint.2025.105953.
Sen Zhang 1,  Chengdi Liu 2,  Wan Li 1,  Yizhi Zhang 1,  Yihui Yang 1,  Hong Yang 1,  Ziyuan Zhao 1,  Fang Xu 1,  Wanxin Cao 1,  Xiaoxue Li 1,  Jinhua Wang 3,  Linglei Kong 4,  Guanhua Du 5
Affiliations

Affiliations

  • 1 The State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing, 100050, China; Beijing Key Laboratory of Innovative Drug Discovery and Polymorphic Druggability Research for Cerebrovascular Diseases, Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100050, China.
  • 2 The State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing, 100050, China; Beijing Key Laboratory of Innovative Drug Discovery and Polymorphic Druggability Research for Cerebrovascular Diseases, Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100050, China; Department of Pharmacy, Affiliated Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China.
  • 3 The State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing, 100050, China; Beijing Key Laboratory of Innovative Drug Discovery and Polymorphic Druggability Research for Cerebrovascular Diseases, Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100050, China. Electronic address: wjh@imm.ac.cn.
  • 4 The State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing, 100050, China; Beijing Key Laboratory of Innovative Drug Discovery and Polymorphic Druggability Research for Cerebrovascular Diseases, Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100050, China. Electronic address: konglinglei@imm.ac.cn.
  • 5 The State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing, 100050, China; Beijing Key Laboratory of Innovative Drug Discovery and Polymorphic Druggability Research for Cerebrovascular Diseases, Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100050, China. Electronic address: dugh@imm.ac.cn.
PMID: 39988285 DOI: 10.1016/j.neuint.2025.105953
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.

Keywords

Angiogenesis; HIF-1α/VEGF-A/Notch1 pathway; Ischemic stroke; Kaempferol.

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