Dynamics of LDL accumulation leading to atherosclerosis initiation

Abstract

Objective – Atherosclerosis is caused by the accumulation of LDL at atherosclerosissusceptible sites. This requires LDLs to pass through the endothelium and be retained in the arterial intima, but which process is rate-limiting and predicts atherosclerosis has remained controversial. To answer this question, we performed high-resolution mapping for LDL entry and retention in healthy, pre-atherosclerotic and atherosclerotic mouse arteries. Approach and Results – Rates of LDL entry and retention were measured by injecting fluorescent LDL into mice followed by en face scanning and whole-mount confocal microscopy of the aortic arch after 1 hour (entry) and 18 hours (retention). Measurements were performed in groups of pre-atherosclerotic mice after short-term hypercholesterolemia and in normocholesterolemic mice with a similar clearance rate of the fluorescent LDL probe. We found that rates of LDL entry and retention under normal and pre-atherosclerotic conditions are dissociated and divide the aortic arch into three zones: an outer arch zone with low LDL entry and LDL retention, and subdivisions of the inner arch region consisting of a border zone with high LDL entry and high LDL retention and a central inner arch zone with intermediate LDL entry and saturable LDL retention. These characteristics predicted susceptibility to atherosclerosis, which was low in the outer zone, high in the border zone, and intermediate in the central inner zone. Saturation of LDL retention in the central inner zone was intrinsic to the arterial wall and was lost with the onset of atherosclerosis. Conclusion – Rates of LDL entry and retention in arteries are dissociated and provide distinct information on atherosclerosis susceptibility. Combined, they predict where and when atherosclerosis develops in the mouse aortic arch.