Our previously published research demonstrated that hematopoietic deficiency of the chemokine-like receptor ChemR23 led to a reduced lesion size and increased proportion of anti-inflammatory M2 macrophages in murine models. However, observations from studies using systemic ChemR23-deficient animals suggest that ChemR23 may have a cell-specific function within the context of atherosclerosis. To explore this hypothesis, we examined the specific role of ChemR23 in vascular cells.

Using a knockout/knock-in reporter mouse model we transplanted bone marrow from Apolipoprotein E-deficient (Apoe-/-) into both Apoe-/- and Apoe-/-ChemR23eGFP/eGFP mice, rendering these mice deficient in somatic ChemR23 expression, mice were fed a Western diet (WD) for 6 or 12 weeks. Lesions characteristic and morphology was examined via histological staining, the aorta also underwent bulk RNA sequencing. The functional role of ChemR23 was further examined by studying human aortic SMCs (HASMCs) using a ChemR23 inhibitor α-NETA, or ligand chemerin 9.

Mice, somatic ChemR23 loss led to significantly larger atherosclerotic lesions and increased lipid accumulation at both 6 and 12 weeks WD. Histological analysis revealed that, loss of ChemR23 resulted in enhanced migration of smooth muscle cells (SMCs) into the plaque, as well as an increase in the formation of SMC-derived foam cells (SMFCs). Bulk RNA sequencing showed that without vascular ChemR23, atherosclerotic pathways and genes for synthetic, athero-progressive smooth muscle cell (SMC) phenotypes are upregulated. In vitro experiments with HASMCs treated with α-NETA, indicated increased cholesterol uptake and reduced efflux, implying that blocking ChemR23 favors SMC-derived foam cell (SMFC) formation. α-NETA also boosted the expression of athero-progressive genes like KLF4, CD36, and MAC2 in HASMCs and enhanced their migration, more so than when treated with chemerin 9, a ChemR23 activator, after INF-γ pre-treatment.

In a therapeutic study, ApoE-deficient mice received α-NETA, chemerin 9, or a vehicle via osmotic pump during a 4-week Western diet. Both treatments reduced lesion sizes but showed unique plaque traits and mechanisms, indicating the need for more research. Our results underscore ChemR23's key role in vascular smooth muscle cell phenotypic regulation, marking it as a promising target for atherosclerosis treatment.