ChemR23 prevents phenotypic switching of vascular smooth muscle cells into macrophage like foam cells in atherosclerosis.
Publisher DOI
PubMed ID
41264461
Abstract
Objective
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.Methods And Results
Mice with a non-hematopoietic cell ChemR23 deficiency due to bone marrow transplantation of Apolipoprotein E deficient bone marrow into irradiated ChemR23e/e Apoe-/- double deficient recipient mice (Apoe-/- ►ChemR23e/e Apoe-/-) were fed a Western Diet for 6- or 12-weeks. Subsequent analysis revealed an increased lesion size and enhanced VSMC proliferation and VSMC foam cells in Apoe-/- ►ChemR23e/e Apoe-/-mice. Bulk RNA sequencing of adventitia-stripped aortas of Apoe-/- ►ChemR23e/e Apoe-/-mice exposed an increase in gene expression of synthetic VSMC markers such as Lgals3 and Cd68, while contractile genes were downregulated. Likewise, single-cell transcriptome data from advanced human atherosclerotic plaques uncovered the highest ChemR23 expression in contractile VSMCs while its expression in synthetic VSMCs was markedly reduced. In vitro, treatment of human aortic smooth muscle cells (HASMCs) with α-NETA, a small molecule inhibitor of ChemR23, increased synthetic gene expression but downregulated expression of TGFB, ABCA1, ABCG1 and SRB1. Further, α-NETA-treated HASMCs downregulated TGFB secretion, increased cholesterol uptake but decreased cholesterol efflux, and showed enhanced cell proliferation. Agonizing ChemR23 with its bona fide ligand chemerin 9 (C9) had no effect on synthetic gene expression but mitigated the effects of α-NETA on gene expression, cholesterol uptake, efflux, and cell proliferation. In vivo, both α-NETA and C9 treatment of Apoe-/- mice over 4 weeks WD revealed therapeutic potential. C9 reduced general inflammatory burden while α-NETA promoted an atheroprotective M2 macrophage phenotype.Conclusions
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.
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.Methods And Results
Mice with a non-hematopoietic cell ChemR23 deficiency due to bone marrow transplantation of Apolipoprotein E deficient bone marrow into irradiated ChemR23e/e Apoe-/- double deficient recipient mice (Apoe-/- ►ChemR23e/e Apoe-/-) were fed a Western Diet for 6- or 12-weeks. Subsequent analysis revealed an increased lesion size and enhanced VSMC proliferation and VSMC foam cells in Apoe-/- ►ChemR23e/e Apoe-/-mice. Bulk RNA sequencing of adventitia-stripped aortas of Apoe-/- ►ChemR23e/e Apoe-/-mice exposed an increase in gene expression of synthetic VSMC markers such as Lgals3 and Cd68, while contractile genes were downregulated. Likewise, single-cell transcriptome data from advanced human atherosclerotic plaques uncovered the highest ChemR23 expression in contractile VSMCs while its expression in synthetic VSMCs was markedly reduced. In vitro, treatment of human aortic smooth muscle cells (HASMCs) with α-NETA, a small molecule inhibitor of ChemR23, increased synthetic gene expression but downregulated expression of TGFB, ABCA1, ABCG1 and SRB1. Further, α-NETA-treated HASMCs downregulated TGFB secretion, increased cholesterol uptake but decreased cholesterol efflux, and showed enhanced cell proliferation. Agonizing ChemR23 with its bona fide ligand chemerin 9 (C9) had no effect on synthetic gene expression but mitigated the effects of α-NETA on gene expression, cholesterol uptake, efflux, and cell proliferation. In vivo, both α-NETA and C9 treatment of Apoe-/- mice over 4 weeks WD revealed therapeutic potential. C9 reduced general inflammatory burden while α-NETA promoted an atheroprotective M2 macrophage phenotype.Conclusions
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.
Date Issued
2026-03-16
Publication Type
Article
Subject(s)
Subjects
ChemR23
•
atherosclerosis
•
phenotypic switching
•
vascular smooth muscle cell
Language(s)
en
Author(s)
Triantafyllidou, Vasiliki | |
Jansen, Yvonne | |
Yan, Yi | |
Maas, Sanne L | |
Gold, Christoph | |
Farina, Floriana M | |
Bayer, Batoul | |
Bartelt, Alexander | |
Wettich, Justus | |
Maegdefessel, Lars | |
Sachs, Nadia | |
Noels, Heidi | |
Santovito, Donato | |
van der Vorst, Emiel P C |
Additional Credits
Journal
Cardiovascular Research
Publisher
Oxford University Press
ISSN
1755-3245
0008-6363
Related Collection(s)
Access(Rights)
open.access