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

PLoS One. 2015 Oct 5;10(10):e0138833. doi: 10.1371/journal.pone.0138833. eCollection 2015.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aorta / cytology
  • Aorta / metabolism*
  • Calcium / metabolism
  • Calcium / pharmacology*
  • Cells, Cultured
  • Chondrogenesis / drug effects
  • Core Binding Factor Alpha 1 Subunit / biosynthesis
  • Core Binding Factor Alpha 1 Subunit / genetics
  • Extracellular Matrix Proteins / biosynthesis
  • Extracellular Matrix Proteins / genetics
  • Female
  • Gene Expression Regulation / drug effects
  • Humans
  • Male
  • Middle Aged
  • Muscle, Smooth, Vascular / cytology
  • Muscle, Smooth, Vascular / metabolism*
  • Myocytes, Smooth Muscle / drug effects
  • Myocytes, Smooth Muscle / metabolism*
  • Osteoblasts / cytology
  • Osteogenesis / drug effects
  • Phenethylamines / pharmacology
  • Phosphoproteins / biosynthesis
  • Phosphoproteins / genetics
  • Propylamines / pharmacology
  • Pulsatile Flow / physiology*
  • Receptors, Calcium-Sensing / agonists
  • Receptors, Calcium-Sensing / antagonists & inhibitors
  • Receptors, Calcium-Sensing / genetics
  • Receptors, Calcium-Sensing / physiology*
  • Recombinant Fusion Proteins / biosynthesis
  • Stress, Mechanical
  • Transfection
  • Vascular Calcification / physiopathology
  • Vascular Calcification / prevention & control*
  • Young Adult

Substances

  • CASR protein, human
  • Core Binding Factor Alpha 1 Subunit
  • DMP1 protein, human
  • Extracellular Matrix Proteins
  • N-(2-chlorophenylpropyl)-1-(3-methoxyphenyl)ethylamine
  • Phenethylamines
  • Phosphoproteins
  • Propylamines
  • RUNX2 protein, human
  • Receptors, Calcium-Sensing
  • Recombinant Fusion Proteins
  • Calcium

Grants and funding

This study was funded by an unrestricted grant from AMGEN (www.amgen.co.uk <http://www.amgen.co.uk/>). AMGEN had no role in the design of the present study, data collection or analysis, the decision to publish, or the preparation of the manuscript. TFH is funded by the NIHR Cambridge Biomedical Research Centre. DZ has received speaking honoraria from AMGEN. TFH has served as consultant for AMGEN.