Figure 12.

Overview of the mechanisms by which defective VSMC autophagy accelerates senescence and promotes postinjury neointima formation and diet-induced atherogenesis. SQSTM1 accumulation in autophagy defective VSMCs triggers NFE2L2 activation and transcription of multiple antioxidative enzymes including GSTA and NQO1. Upregulation of GSTA and NQO1 promotes VSMC survival against oxidative stress under defective autophagy conditions. SQSTM1 accumulation in autophagy defective VSMCs triggers the development of stress-induced premature senescence. Autophagy defective VSMCs are characterized by CDKN2A-RB-mediated G₁ proliferation arrest, increased migration and changes in VSMC phenotype. Enhanced migration is associated with increased secretion of MMP9, TGFB and CXCL12. The phenotype of autophagy defective VSMCs is defined by nuclear and cellular hypertrophy, and by increased collagen content. Defective autophagy in VSMCs accelerates postinjury neointima formation and diet-induced atherogenesis.