Extracellular matrix contributes to macrophage foam cell formation and atherosclerosis

Abstract

During early atherogenesis, low density lipoprotein (LDL) induces the accumulation of cholesterol and oxysterols in arterial macrophages, and in the subendothelial accumulation of atherogenic lipoproteins in extracellular matrix (ECM), takes place.
Retention of LDL and oxidized LDL (Ox-LDL) to ECM is mediated by the ECM proteoglycans (PGs), which in the presence of Lipoprotein Lipase (LPL, acting as a bridging element), bind the lipoproteins. The structures of the ECM proteoglycans, as well as the lipoproteins binding sites for PGs determine the extent of the interaction between ECM PGs and lipoproteins. Following its retention to the ECM, Ox-LDL is taken up by activated macrophages at enhanced rate, leading to cellular accumulation of cholesterol and oxysterols in arterial wall macrophages. Moreover, LDL oxidation in the arterial wall can also take place after lipoprotein retention to ECM PGs. In this case, retained Ox-LDL can be taken up by macrophage after its release from ECM PGs; but also as a complex of Ox-LDL with ECM PGs. The amount and composition of ECM, produced by all major cells of the arterial wall (monocyte-derived macrophages, endothelial cells and smooth muscle cells), determine the extent of lipoproteins cellular uptake. We have demonstrated that under oxidative stress, ECM PGs secretion from macrophages, binding of Ox-LDL to the ECM and uptake of the retained lipoproteins by macrophages are all significantly increased. Altogether, these processes contribute to macrophage foam cell formation and accelerated atherosclerosis.