Dual Lineage Tracing Identifies Cellular Mechanisms Underlying Radiation-Associated Changes in Atherosclerotic Lesion Composition

<b>What Is New?</b> We developed a dual lineage-tracing mouse model that enables simultaneous fate mapping of smooth muscle cells and endothelial cells within the same atherosclerotic lesion.This model reveals coordinated arterial cell wall responses to vascular injury that cannot be resolved using single lineage-tracing approaches. Extending prior observations, we show that irradiation-induced inflammatory reprogramming of smooth muscle cells and endothelial-to-mesenchymal transition of endothelial cells towards a smooth muscle cell-like state are associated with reduced total lesion collagen content and decreased overall ACTA2 ⁺ fibrous cap cellularity. This dual lineage-tracing mouse establishes a broadly applicable model for investigating arterial wall cell dynamics across diverse vascular disease states. <b>What Are the Clinical Implications?</b> Cancer therapies involving radiotherapy are associated with increased long-term risk of atherosclerotic cardiovascular disease.Our findings identify a potential cellular mechanism underlying this risk, in which irradiation-induced smooth muscle cell loss is not functionally compensated by endothelial-to-mesenchymal transition toward a SMC-like state.This dual lineage-tracing model provides a tool to evaluate how cancer therapies and other vascular stressors may alter arterial wall cell fate and indices of plaque stability in atherosclerosis and other vascular diseases.