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. 2022 Jun 13;19(12):783–797. doi: 10.1038/s41569-022-00718-5

Fig. 2. Non-canonical WNT signalling in atherosclerosis.

Fig. 2

Non-canonical WNT ligands, such as WNT5A, can enter the vascular wall from the circulation and are also released by vascular macrophages and the perivascular adipose tissue (PVAT). In endothelial cells, binding of non-canonical WNT ligands to their receptors leads to the upregulation of the expression of intracellular adhesion molecule 1 (ICAM1) and vascular cell adhesion molecule 1 (VCAM1), which promotes monocyte recruitment to the arterial intima. Non-canonical WNT signalling in endothelial cells also induces the activation of NADPH oxidases (NOX), which leads to increased production of reactive oxygen species (ROS), activation of pro-inflammatory redox signalling, reduced nitric oxide (NO) bioavailability and endothelial dysfunction. In monocytes and macrophages, non-canonical WNT signalling promotes pro-inflammatory activation, uptake of oxidized LDL (oxLDL) and foam cell formation, and production of pro-inflammatory cytokines such as C-C motif ligand 2 (CCL2), IL-1β and IL-6. In vascular smooth muscle cells (VSMCs), non-canonical WNT signalling induces a switch from a contractile to a synthetic phenotype and increases cell migration via ROS signalling, thereby promoting the migration of synthetic VSMCs into the atherosclerotic plaque, where they produce extracellular matrix (ECM) components and matrix metalloproteinases (MMPs). These mechanisms interact in complex ways to establish a vicious cycle, directly promoting atherogenesis and plaque instability.