Arterial Expression of the Calcium-Sensing Receptor Is Maintained by Physiological Pulsation and Protects against Calcification.

Guerman Molostvov,Rosemary Bland,Thomas F Hiemstra,Daniel Zehnder,Simon Fletcher,Giovanna Valenti

doi:10.1371/journal.pone.0138833

Guerman Molostvov, Rosemary Bland + Show 4 more

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https://doi.org/10.1371/journal.pone.0138833

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Abstract

Vascular calcification (VC) is common in chronic kidney disease (CKD) and contributes to cardiovascular mortality. The calcium-sensing receptor (CaSR) is present in human artery, senses extracellular calcium and may directly modulate VC. Objective: to investigate the association between arterial cyclic strain, CaSR expression and VC. Methods and Results: human aortic smooth muscle cells (HAoSMC) were cultured under static or strained conditions, with exposure to CaSR agonists, the calcimimetic R568, and after CaSR silencing and over-expression. High extracellular calcium reduced CaSR expression and promoted osteochondrogenic transformation and calcium deposition. This was partially prevented by cyclic strain and exposure to R568. CaSR silencing enhanced calcification and osteochondrogenic transformation, whereas CaSR over-expression attenuated this procalcific response, demonstrating a central role for the CaSR in the response to cyclic strain and regulation of VC. In arterial explants from CKD patients (n = 11) and controls (n = 9), exposure to R568 did not significantly alter calcium deposition, osteochondrogenic markers or total artery calcium content. Conclusions: physiological mechanical strain is important for arterial homeostasis and may protect arteries from VC. The beneficial effects of cyclic strain may be mediated via the CaSR.

Highlights

The presence of arterial calcification is a powerful independent predictor of cardiovascular death in the general population [1] and in patients with chronic kidney disease (CKD) [2,3]
To assess whether exposure of human aortic smooth muscle cells (HAoSMC) to calcium-sensing receptor (CaSR) agonists impacted on their propensity to calcify, HAoSMC were cultured under control conditions and upon exposure to calcium and the non-calcium CaSR agonist, gadolinium, as follows: Control (Ca2+ 1.1mmol/L), moderate (Ca2+ 2.0mmol/L), and high calcium (5mmol/L), hereafter denoted Control, Ca2 and Ca5 respectively; and Gadolinium 0.05mmol/L with either Ca2+ 1.1mmol/L or Ca2+ 2.0mmol/L, denoted Gd and Gd+Ca2 respectively
Significant calcification occurred in Gd (3.4%, 95% confidence intervals (95%CI) 2.3–4.5%, p = 0.0001) and Gd+Ca2 HAoSMC (4.3%, 95%CI 3.5–5.2%, p

Summary

Introduction

The presence of arterial calcification is a powerful independent predictor of cardiovascular death in the general population [1] and in patients with chronic kidney disease (CKD) [2,3]. Arterial calcification is present in almost 100% of patients with end-stage CKD [4,5]. In CKD disorders of mineral metabolism contribute to arterial calcification and diminished vascular compliance [6], leading to increased cardiac workload, heart failure, and sudden cardiac death [4]. Vascular calcification (VC) is a regulated, cell-mediated process similar to bone formation [7]. Several factors promote the transformation of contractile vascular smooth muscle cells.

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