Distribution of major ECM components in the normal artery wall and different stages of atherosclerosis. Composition of ECM varies in different layers of the artery wall and at different stages of atherosclerosis. (a) Collagen I and decorin in the adventitia, along with collagens I and III, elastic fibers, and versican in the medial layer make up the majority of ECM in normal arterial walls. (b) Diffuse intimal thickening (DIT) is a thick layer of smooth muscle cells (SMCs) and proteoglycans (PGs) present in atherosclerosis-prone arteries beginning from birth. Biglycan, decorin, and versican secreted mainly by SMCs are the primary PGs in DIT, where biglycan and decorin are located in the deep intima and versican mainly in the superficial intima. (c) ApoB-containing lipoproteins that enter from the plasma via transcytosis through the endothelium are retained in the deep intima in early atherosclerosis due to a charge-charge interaction between apoB and glycosaminoglycan side chains of biglycan and decorin in the deep intima. (d) Trapped lipoproteins are modified, aggregated, and taken up by surrounding SMCs and macrophages to make foam cells (macrophages are omitted to emphasize the role of the ECM). Perlecan in mouse atheromas also binds lipoproteins but does not participate in this retention in humans. (e) Apoptosis/necrosis of foam cells leads to formation of a necrotic core in advanced atherosclerotic plaques, with versican being prominent at the edge. (f) Stable plaques are defined by the presence of a thick fibrous cap lying between the necrotic core and the luminal surface of the plaque. The fibrous caps consist of more differentiated SMCs and are enriched in versican, biglycan, and collagen type I, with lesser amounts of decorin and hyaluronan. (g) Unstable plaques with little or no fibrous cap show an intense staining for hyaluronan, versican, and collagen type III at the site of erosion and weak staining for biglycan and decorin