Metformin inhibits intracranial aneurysm formation and progression by regulating vascular smooth muscle cell phenotype switching via the AMPK/ACC pathway

  • J Neuroinflammation. 2020 Jun 16;17(1):191. doi: 10.1186/s12974-020-01868-4.
Sichen Li  1  2 ,  Yuan Shi  1  2 ,  Peixi Liu  1  2 ,  Yaying Song  3  4 ,  Yingjun Liu  1  2 ,  Lingwen Ying  5 ,  Kai Quan  1  2 ,  Guo Yu  1  2 ,  Zhiyuan Fan  1  2 ,  Wei Zhu  6  7
Affiliations
  • 1. Department of Neurosurgery, Huashan Hospital, Fudan University, 12 Wulumuqi Road Middle, Shanghai, 200040, People's Republic of China.
  • 2. Neurosurgical Institute of Fudan University, Shanghai, People's Republic of China.
  • 3. Department of Neurology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, No. 160 Pujian Rd, Shanghai, 200025, People's Republic of China.
  • 4. Neuroscience and Neuroengineering Research Center, Med-X Research Institute and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, People's Republic of China.
  • 5. Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, People's Republic of China.
  • 6. Department of Neurosurgery, Huashan Hospital, Fudan University, 12 Wulumuqi Road Middle, Shanghai, 200040, People's Republic of China. [email protected].
  • 7. Neurosurgical Institute of Fudan University, Shanghai, People's Republic of China. [email protected].
PMID: 32546267 DOI: 10.1186/s12974-020-01868-4
Abstract

Background: The regulation of vascular smooth muscle cell (VSMC) phenotype plays an important role in intracranial aneurysm (IA) formation and progression. However, the underlying mechanism remains unclear. Metformin is a 5' AMP-activated protein kinase (AMPK) agonist that has a protective effect on vasculature. The present study investigated whether metformin modulates VSMC phenotype switching via the AMPK/Acetyl-CoA Carboxylase (ACC) pathway during IA pathogenesis.

Methods: Adult male Sprague-Dawley rats (n = 80) were used to establish an elastase-induced IA model. The effects of metformin on AMPK activation and VSMC phenotype modulation were examined. We also established a platelet-derived growth factor (PDGF)-BB-induced VSMC model and analyzed changes in phenotype including proliferation, migration, and Apoptosis as well as AMPK/ACC axis activation under different doses of metformin, AMPK antagonist, ACC antagonist, and their combinations.

Results: Metformin decreased the incidence and rupture rate of IA in the rat model and induced a switch in VSMC phenotype from contractile to synthetic through activation of the AMPK/ACC pathway, as evidenced by upregulation of VSMC-specific genes and decreased levels of pro-inflammatory cytokines. AMPK/ACC axis activation inhibited the proliferation, migration, and Apoptosis of VSMCs, in which phenotypic switching was induced by PDGF-BB.

Conclusions: Metformin protects against IA formation and rupture by inhibiting VSMC phenotype switching and proliferation, migration, and Apoptosis. Thus, metformin has therapeutic potential for the prevention of IA.

Keywords
AMPK; Intracranial aneurysm; Metformin; Phenotype modulation; Vascular smooth muscle cell.
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