Abstract
BackgroundThe 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.MethodsAdult 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.ResultsMetformin 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.ConclusionsMetformin 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.
Highlights
Intracranial aneurysm (IA) is a cerebrovascular disease with a global prevalence of up to 7% [1]
vascular smooth muscle cell (VSMC) in human intracranial aneurysm (IA) samples switch from a contractile to synthetic phenotype with the downregulation of p-5′ AMP-activated protein kinase (AMPK) To investigate the relationship between AMPK activation and phenotype modulation in IA, we evaluated αSMA and p-AMPK expression levels in human IA and superficial temporal artery (STA) tissues
These findings suggest that VSMCs undergo phenotype switching in IA, which is accompanied by decreased expression of p-AMPK
Summary
Intracranial aneurysm (IA) is a cerebrovascular disease with a global prevalence of up to 7% [1]. The mechanisms underlying IA formation and rupture remain unclear but are thought to be related to pathological changes in vasculature caused by endothelial dysfunction, extracellular matrix remodeling, and phenotype switching of vascular smooth muscle cells (VSMCs) [3,4,5,6,7,8,9,10,11]. An AMPK activator, exerts a cardioprotective function by reducing the incidence of cardiovascular events [21] It is unclear whether it provides protection against IA. The regulation of vascular smooth muscle cell (VSMC) phenotype plays an important role in intracranial aneurysm (IA) formation and progression. The present study investigated whether metformin modulates VSMC phenotype switching via the AMPK/acetyl-CoA carboxylase (ACC) pathway during IA pathogenesis
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