Calcification is associated with loss of functional calcium-sensing receptor in vascular smooth muscle cells
Open Access
- 13 October 2008
- journal article
- research article
- Published by Oxford University Press (OUP) in Cardiovascular Research
- Vol. 81 (2), 260-268
- https://doi.org/10.1093/cvr/cvn279
Abstract
Vascular calcification (VC) is highly correlated with increased morbidity and mortality in advanced chronic kidney disease (CKD) patients. Allosteric modulation of the calcium-sensing receptor (CaR) by calcimimetics inhibits VC in animal models of advanced CKD. Here, we investigated the expression of the CaR in the vasculature and tested the ability of calcimimetics to prevent vascular smooth muscle cell (VSMC) calcification in vitro. Immunohistochemical staining demonstrated that CaR protein is present in VSMC in normal, non-calcified human arteries. In contrast, low levels of CaR immunoreactivity were detected in atherosclerotic, calcified arteries. Immunfluorescence and immunoblotting revealed that CaR protein was also expressed by human and bovine VSMC in vitro. Acute stimulation of VSMC with increased Ca2+ stimulated extracellular signal-regulated kinase (ERK1/2) phosphorylation, suggesting that the VSMC CaR is functional. VSMC CaR expression decreased when these cells deposited a mineralized matrix or following 24 h incubation in mineralization medium with increased (i.e. 1.8 or 2.5 mM) Ca2+. Culturing VSMC in mineralization medium containing 1.8 and 2.5 mM Ca2+ or with the membrane-impermeant CaR agonist Gd3+ enhanced mineral deposition compared with that observed in 1.2 mM Ca2+. Over-expression of dominant-negative (R185Q) CaR enhanced, whereas the calcimimetic R-568 attenuated, VSMC mineral deposition. These results demonstrate that: (i) VSMCs express a functional CaR; (ii) a reduction in CaR expression is associated with increased mineralization in vivo and in vitro; (iii) calcimimetics decrease mineral deposition by VSMC. These data suggest that calcimimetics may inhibit the development of VC in CKD patients.This publication has 48 references indexed in Scilit:
- Vascular CalcificationCirculation, 2008
- Vascular CalcificationCirculation Research, 2006
- Molecular Mechanisms of Vascular CalcificationArteriosclerosis, Thrombosis, and Vascular Biology, 2006
- Arteriosclerosis, vascular calcifications and cardiovascular disease in uremiaCurrent Opinion in Nephrology and Hypertension, 2005
- Evolution and modulation of age-related medial elastocalcinosis: Impact on large artery stiffness and isolated systolic hypertensionCardiovascular Research, 2005
- Regulation of Vascular CalcificationCirculation Research, 2005
- Human Vascular Smooth Muscle Cells Undergo Vesicle-Mediated Calcification in Response to Changes in Extracellular Calcium and Phosphate ConcentrationsJournal of the American Society of Nephrology, 2004
- Uremia induces the osteoblast differentiation factor Cbfa1 in human blood vesselsKidney International, 2003
- Osteo/Chondrocytic Transcription Factors and Their Target Genes Exhibit Distinct Patterns of Expression in Human Arterial CalcificationArteriosclerosis, Thrombosis, and Vascular Biology, 2003
- Association of serum phosphorus and calcium x phosphate product with mortality risk in chronic hemodialysis patients: A national studyAmerican Journal of Kidney Diseases, 1998