Atherogenesis, Transcytosis, and the Transmural Cholesterol Flux: A Critical Review

Figure 2

Transmural cholesterol flux-driven plaque formation. (a) Cross-section through a healthy artery with fully functioning reverse cholesterol transport (RCT). The yellow arrows represent transmural cholesterol flux (TCF) of lipoproteins and cholesterol from the vasa vasorum (vv) in the adventitia, maybe through fenestra in the elastic laminas, to the vascular smooth muscle cells (VSMCs) in the avascular media, and finally to the apical endothelial membrane. (b) The result of impaired endothelial RCT: as the intima strives to maintain the TCF, excess cholesterol slowly accumulates in the subendothelial layer by binding to intimal extracellular matrix proteins [131] and initiates plaque formation. (c) A magnified cutaway of the initial plaque shows smooth muscle cells migrating from the media into the intima and their transdifferentiation into cholesterol-loaded foam cells [76]. The hypoxia in the underlying media, caused by the increased endothelial cholesterol concentration, stimulates neovascularization and vv expansion [41]. Both VSMCs migration into the intima and vv expansion can precede plaque formation [76, 118]. (d) The oxidation and enzymatic modification (i.e., production of enzymatically modified LDL‒eLDL) of the accumulating lipids in the growing plaque trigger the immune system [84, 85] and the consequent inflammation and migration of monocytes and T-cells from the lumen. The monocytes differentiate into cholesterol scavenging macrophages which eventually become foam cells [120]. This inflammation marks the formation of a full-fledged atherosclerotic plaque.