Fig. 3

VSMCs phenotype switching in advanced atherosclerotic plaque. Due to damage or dysfunction of endothelial cells, circulating LDL (including ApoB) passes through the endothelial barrier into the subendothelium and is subsequently captured by HSPGs in the ECM. Subsequently, LDL is gradually oxidized into ox-LDL under free radicals or other oxidants. The accumulation of ox-LDL induces the migration of macrophages and monocytes to the lesion area. Macrophages engulf oxidized lipids and necrotic cells in the lesion, secrete inflammatory cytokines, and transform to foam cells. Finally, these foam cells are apoptotic and coalesce into a lipid-rich necrotic core in subendothelium. Macrophage-like VSMCs also engulf lipid and necrotic cell debris to form foam cells. However, the phagocytosis of macrophage-like VSMCs is lower than that of macrophages, disrupting the efficiency of lipid disposal and debris clearance in plaques, thereby exacerbating the formation of atherosclerotic plaques. Meanwhile, ox-LDL and various inflammatory cytokines (such as PDGF, TNF-α, IFN-γ, IL-1, MMP-2/9, etc.) can stimulate VSMCs to migrate from tunica media to tunica intima to form neointima and phenotype transformation occurred in the process The contractile VSMCs first transform into LGALS3 + VSMCs, this kind of cell is also known as pioneer cells, Stem/Endothelial/Macrophage (SEM) cells, or fibromyocytes. These transitional VSMCs can synthesize ECM, participate in the formation of fibrous cap, and can also transform into macrophage-like VSMCs, osteogenic VSMCs, and other types of VSMCs. Macrophage-like VSMCs derived foam cells secrete MMPs to destroy ECM in the fibrous cap, and osteogenic VSMCs participate in calcification of lipid necrotic core, both of which are generally thought to aggravate plaque instability. VEC, vascular endothelial cell; VSMC, vascular smooth muscle cell; ECM, extracellular matrix; LGALS3, galectin-3; LDL, low density lipoprotein; ox-LDL, oxidized low-density lipoprotein; HSPG, heparan sulfate proteoglycan; ApoB, apolipoprotein B; PDGF, platelet derived growth factor; TNF-α, tumor necrosis factor alpha; IFN-γ, interferon-gamma; IL-1, interleukin 1; MMPs, metalloproteases