The G-protein coupled receptor ChemR23 determines smooth muscle cell phenotypic switching to enhance high phosphate-induced vascular calcification

Abstract

Aims Vascular calcification, a marker of increased cardiovascular risk, is an active process orchestrated by smooth muscle cells. Observational studies indicate that omega-3 fatty acids protect against vascular calcification, but the mechanisms are unknown. The G-protein coupled receptor ChemR23 transduces the resolution of inflammation induced by the omega-3-derived lipid mediator resolvin E1. ChemR23 also contributes to osteoblastic differentiation of stem cells and bone formation, but its role in vascular calcification is unknown. The aim of this study was to establish the role of ChemR23 in smooth muscle cell fate and calcification Methods and results Gene expression analysis in epigastric arteries derived from patients with chronic kidney disease and vascular calcification revealed that ChemR23 mRNA levels predicted a synthetic smooth muscle cell phenotype. Genetic deletion of ChemR23 in mice prevented smooth muscle cell de-differentiation. ChemR23-deficient smooth muscle cells maintained a non-synthetic phenotype and exhibited resistance to phosphate-induced calcification. Moreover, ChemR23-deficient mice were protected against vitamin D3-induced vascular calcification. Resolvin E1 inhibited smooth muscle cell calcification through ChemR23. Introduction of the Caenorhabditis elegans Fat1 transgene, leading to an endogenous omega-3 fatty acid synthesis and hence increased substrate for resolvin E1 formation, significantly diminished the differences in phosphate-induced calcification between ChemR23+/+ and ChemR23−/− mice. Conclusion This study identifies ChemR23 as a previously unrecognized determinant of synthetic and osteoblastic smooth muscle cell phenotype, favouring phosphate-induced vascular calcification. This effect may be of particular importance in the absence of ChemR23 ligands, such as resolvin E1, which acts as a calcification inhibitor under hyperphosphatic conditions.

Renal Chemerin Expression is Induced in Models of Hypertensive Nephropathy and Glomerulonephritis and Correlates with Markers of Inflammation and Fibrosis

“…This seems controversial, as CKD induces premature vascular aging with vascular calcification and increased arterial stiffness [46]. In addition, previous studies had indicated a role of CmklR1 for the vascular smooth muscle cell (VSMC) atherosclerotic phenotype [47], characterized by vascular inflammation and intimal hyperplasia [48,49]. Surprisingly, chemerin seemed to inhibit atherogenesis through CmklR1 [48,50].…”

Semicarbazide-Sensitive Amine Oxidase Increases in Calcific Aortic Valve Stenosis and Contributes to Valvular Interstitial Cell Calcification

“…Adjacent pieces were embedded in paraffin for histological analysis. Macroscopic dissection was performed dividing each valve into healthy, thickened, or calcified regions as previously described [17][18][19].…”

Inflammation and Premature Ageing in Chronic Kidney Disease

“…The endocrine fibroblast growth factor-23 (FGF-23)-klotho pathway (Figures 1 and 2) is important for the resorption of phosphate in the kidney and is dysregulated in CKD. Decreased renal clearance produces a relative overload of inorganic phosphate (P i ), which results in hyperphosphatemia and contributes to systemic inflammation and vascular calcification/early vascular ageing (EVA) [19] ( Figure 2). Hyperphosphatemia promotes endothelial dysfunction and trans-differentiation of vascular Toxins 2020, 12, 227 3 of 21 smooth muscle cells (VSMC) into osteoblast-like cells [20].…”