ChemR23 prevents phenotypic switching of vascular smooth muscle cells into macrophage like foam cells in atherosclerosis
Hematopoietic ChemR23 deficiency was shown to reduce atherosclerotic lesions by increasing M2 macrophages, but conflicting results in systemically deficient mice suggest a cell-specific function of ChemR23. Therefore, we aimed to study the role of ChemR23 particularly on vascular smooth muscle cells (VSMCs) in atherosclerosis. Using bone marrow transplantation, mice with non-hematopoietic ChemR23 deficiency developed larger atherosclerotic lesions with increased VSMC proliferation and foam cell formation, accompanied by a shift from contractile to synthetic VSMC gene expression. Consistently, human plaque single-cell data showed high ChemR23 expression in contractile VSMCs and reduced expression in synthetic VSMCs, while ChemR23 inhibition in HASMCs promoted a synthetic, proliferative, and cholesterol-retentive phenotype that was counteracted by the ChemR23 agonist chemerin 9. In vivo, both ChemR23 inhibition and agonism demonstrated therapeutic potential in Apoe-/- mice, with chemerin 9 reducing inflammation and α-NETA favoring an atheroprotective M2 macrophage response. These findings suggest a critical role of ChemR23 in regulating VSMC phenotype switching thereby affecting atherosclerosis and suggest ChemR23 as a therapeutic target to either modulate inflammation (C9) or macrophage polarization (α-NETA) in atherosclerotic disease.
Evans et al., Cardiovasc Res. 2025