Senescent cells suppress innate smooth muscle cell repair functions in atherosclerosis

Senescent cells (SNCs) degenerate the fibrous cap that normally prevents atherogenic plaque rupture, a leading cause of myocardial infarction and stroke. Here we explore the underlying mechanism using pharmacological or transgenic approaches to clear SNCs in the Ldlr^–/– mouse model of atherosclerosis. SNC clearance reinforced fully deteriorated fibrous caps in highly advanced lesions, as evidenced by restored vascular smooth muscle cell (VSMC) numbers, elastin content and overall cap thickness. We found that SNCs inhibit VSMC promigratory phenotype switching in the first interfiber space of the arterial wall directly beneath the atherosclerotic plaque, thereby limiting lesion entry of medial VSMCs for fibrous cap assembly or reinforcement. SNCs do so by antagonizing insulin-like growth factor (IGF)-1 through the secretion of IGF-binding protein-3. These data indicate that the intermittent use of senolytic agents or IGF-binding protein-3 inhibition in combination with lipid-lowering drugs may provide therapeutic benefit in atherosclerosis.