中国神经再生研究(英文版) ›› 2023, Vol. 18 ›› Issue (7): 1553-1562.doi: 10.4103/1673-5374.360245

• 原著:脊髓损伤修复保护与再生 • 上一篇    下一篇

二甲双胍促进老年小鼠脊髓损伤后血管生成和功能恢复 

  

  • 出版日期:2023-07-15 发布日期:2023-01-12
  • 基金资助:
    国家自然科学基金项目(82030071,81874004);长沙市科技重大项目(kh2103008)

Metformin promotes angiogenesis and functional recovery in aged mice after spinal cord injury by adenosine monophosphate-activated protein kinase/endothelial nitric oxide synthase pathway

Jin-Yun Zhao1, 2, 3, 4, Xiao-Long Sheng1, 2, 3, 4, Cheng-Jun Li1, 2, 3, 4, Tian Qin1, 2, 3, 4, Run-Dong He1, 2, 3, 4, Guo-Yu Dai1, 2, 3, 4, Yong Cao1, 2, 3, 4, Hong-Bin Lu2, 3, 4, 5, Chun-Yue Duan1, 2, 3, 4, *, Jian-Zhong Hu1, 2, 3, 4, *   

  1. 1Department of Spine Surgery and Orthopedics, Xiangya Hospital, Central South University, Changsha, Hunan Province, China; 2Key Laboratory of Organ Injury, Aging and Regenerative Medicine of Hunan Province, Changsha, Hunan Province, China; 3National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan Province, China; 4Hunan Engineering Research Center of Sports and Health, Changsha, Hunan Province, China; 5Department of Sports Medicine, Research Centre of Sports Medicine, Xiangya Hospital, Central South University, Changsha, Hunan Province, China
  • Online:2023-07-15 Published:2023-01-12
  • Contact: Jian-Zhong Hu, PhD, jianzhonghu@hotmail.com; Chun-Yue Duan, PhD, docdcy@qq.com.
  • Supported by:
    This work was supported by the Natural Nature Science Foundation of China, Nos. 82030071, 81874004; and the Science and Technology Major Project of Changsha, No. kh2103008 (all to JZH).

摘要:

二甲双胍治疗可恢复脊髓损伤后广泛的生物活性,但其是否也对老年小鼠的脊髓损伤有作用,目前仍不清楚。考虑到血管生成在再生过程中的重要作用,实验假设二甲双胍可通过激活内皮细胞中的单磷酸腺苷活化蛋白激酶/内皮一氧化氮合酶通路,为脊髓损伤老年小鼠的微血管再生提供更有利的微环境。为此,实验以改良重物自由落体打击法建立了挫伤性脊髓损伤青年及老年小鼠模型中,结果显示,衰老会阻碍神经功能恢复和脊髓中血管的形成。然后以二甲双胍干预脊髓微血管内皮细胞,发现其可在体外促进脊髓微血管内皮细胞的迁移和血管形成。进一步体内实验通过腹腔注射二甲双胍对老年脊髓损伤小鼠模型进行治疗,可见其通过增加脊髓中新血管密度,促进内皮细胞增殖及血管生成,从而改善其神经功能。此外,单磷酸腺苷活化蛋白激酶抑制剂化合物C在体内外逆转二甲双胍的作用,由此提示单磷酸腺苷活化蛋白激酶/内皮一氧化氮合酶通路可能参与调节脊髓损伤后二甲双胍对血管生成的作用。上述结果表明,二甲双胍可通过激活单磷酸腺苷活化蛋白激酶/内皮一氧化氮合酶通路通过增强老龄小鼠损伤脊髓局部的血管再生,改善脊髓损伤后的神经功能。

https://orcid.org/0000-0002-6874-4853 (Chun-Yue Duan)

关键词: 二甲双胍, 老年小鼠, 血管生成, 脊髓损伤, 单磷酸腺苷活化蛋白激酶, 内皮一氧化氮合酶, 化合物C, 脊髓微血管内皮细胞

Abstract: Treatment with metformin can lead to the recovery of pleiotropic biological activities after spinal cord injury. However, its effect on spinal cord injury in aged mice remains unclear. Considering the essential role of angiogenesis during the regeneration process, we hypothesized that metformin activates the adenosine monophosphate-activated protein kinase/endothelial nitric oxide synthase pathway in endothelial cells, thereby promoting microvascular regeneration in aged mice after spinal cord injury. In this study, we established young and aged mouse models of contusive spinal cord injury using a modified Allen method. We found that aging hindered the recovery of neurological function and the formation of blood vessels in the spinal cord. Treatment with metformin promoted spinal cord microvascular endothelial cell migration and blood vessel formation in vitro. Furthermore, intraperitoneal injection of metformin in an in vivo model promoted endothelial cell proliferation and increased the density of new blood vessels in the spinal cord, thereby improving neurological function. The role of metformin was reversed by compound C, an adenosine monophosphate-activated protein kinase inhibitor, both in vivo and in vitro, suggesting that the adenosine monophosphate-activated protein kinase/endothelial nitric oxide synthase pathway likely regulates metformin-mediated angiogenesis after spinal cord injury. These findings suggest that metformin promotes vascular regeneration in the injured spinal cord by activating the adenosine monophosphate-activated protein kinase/endothelial nitric oxide synthase pathway, thereby improving the neurological function of aged mice after spinal cord injury. 

Key words: adenosine monophosphate-activated protein kinase/endothelial nitric oxide synthase pathway, angiogenesis, aged mice, compound C, metformin, spinal cord injury