Defective autophagy in vascular smooth muscle cells accelerates senescence and promotes neointima formation and atherogenesis

Abstract

VSMCs were resistant to oxidative stress-induced cell death as compared to controls. This effect was attributed to nuclear translocation of the transcription factor NFE2L2 resulting in upregulation of several antioxidative enzymes. In vivo, defective VSMC autophagy led to upregulation of MMP9, TGFB and CXCL12 and promoted postinjury neointima formation and diet-induced atherogenesis. Lesions of VSMC-specific atg7 knockout mice were characterized by increased total collagen deposition, nuclear hypertrophy, CDKN2A upregulation, RB hypophosphorylation, and GLB1 activity, all features typical of cellular senescence. To conclude, autophagy is crucial for VSMC function, phenotype, and survival. Defective autophagy in VSMCs accelerates senescence and promotes ligation-induced neointima formation and diet-induced atherogenesis, implying that autophagy inhibition as therapeutic strategy in the treatment of neointimal stenosis and atherosclerosis would be unfavorable. Conversely, stimulation of autophagy could be a valuable new strategy in the treatment of arterial disease.