Transcellular permeability of arterial endothelium to plasma LDL, an underexplored target in treating atherosclerosis: Novel insights and potential treatment strategies

Ischaemic heart disease, of which atherosclerosis is the primary substrate, continues to be a leading cause of death globally. Atherosclerosis is characterised by the accumulation of cholesterol, mainly from circulating low-density lipoprotein (LDL), within the arterial wall. LDL influx is determined by the product of two variables: the concentration of LDL in plasma and the permeability of the endothelium to LDL. Lowering the former is the primary therapeutic strategy employed today. Meanwhile, lowering permeability ought to be equally beneficial, and its effect on influx would likely be multiplicative with lipid lowering, but it is currently underexplored as a target in treating atherosclerosis. Advances in electron microscopy have helped improve our understanding of the three primary routes through which LDL permeates the endothelium: transcellular (via passive and active, receptor-mediated transport that involves the movement of LDL as cargo inside caveolae), paracellular (via interendothelial/paracellular junctions), and through cells undergoing mitosis and apoptosis (leaky junctions). We have therefore highlighted in this review, based on recent advances in experimental and translational investigations viable pharmacological agents that modulate transendothelial permeability to LDL as potential treatment options for atherosclerosis.