Pathogenesis of atherosclerosis. (a) In the first stage, low density lipoprotein-cholesterol (LDL) is deposited in the endothelium and undergoes oxidative modification, resulting in oxidized LDL (oxLDL). OxLDL stimulates endothelial cells to express adhesion molecules (vascular cell adhesion molecule-1 (VCAM-1), P-Selectin) and various chemokines (e.g., Monocyte Chemoattractant Protein-1 (MCP-1), Interleukin 8 (IL-8)). This leads to a recruitment of monocytes, which transmigrate into the intima and differentiate to pro-atherogenic macrophages; (b) Macrophages harvest residual oxLDL via their scavenger receptors and add to the endothelial activation and, subsequently, leukocyte recruitment with the secretion of Tumor Necrosis Factor α (TNF-α) and IL-6; (c) The increasing plaque volume promotes neovascularization. Proliferating smooth muscle cells (SMCs) stabilize the nascent fibrous plaque. With deposition of fibrin and activated platelets on the dysfunctional endothelium that expresses tissue factor (TF) and von Willebrand factor (vWF), a pro-thrombotic milieu is formed; (d) Foam cells can undergo apoptosis and release cell-debris and lipids, which will result in the formation of a necrotic core. In addition, proteases secreted from foam cells can destabilize the plaque. This can lead to plaque rupture, in which case extracellular matrix molecules (e.g., collagens, elastin, TF, vWF) catalyze thrombotic events.
(PMC full text: Int J Mol Sci. 2015 May; 16(5): 9749–9769. Published online 2015 )
