Vascular smooth muscle cell differentiation to an osteogenic phenotype involves TRPM7 modulation by magnesium

Augusto C. Montezano, Deborah Zimmerman, Hiba Yusuf, Dylan Burger, Andreia Z. Chignalia, Vishal Wadhera, Frank N. Van Leeuwen, Rhian M. Touyz

Research output: Contribution to journalArticlepeer-review

154 Scopus citations

Abstract

Arterial calcification, common in vascular diseases, involves vascular smooth muscle cell (VSMC) transformation to an osteoblast phenotype. Clinical studies suggest that magnesium may prevent this, but mechanisms are unclear. We assessed whether increasing magnesium levels reduce VSMC calcification and differentiation and questioned the role of the Mg transporter, transient receptor potential melastatin (TRPM)7 cation channels in this process. Rat VSMCs were exposed to calcification medium in the absence and presence of magnesium (2.0 to 3.0 mmol/L) or 2-aminoethoxy-diphenylborate (2-APB) (TRPM7 inhibitor). VSMCs from mice with genetically low (MgL) or high-normal (MgH) [Mg]i were also studied. Calcification was assessed by von Kossa staining. Expression of osteocalcin, osteopontin, bone morphogenetic protein (BMP)-2, BMP-4, BMP-7, and matrix Gla protein and activity of TRPM7 (cytosol:membrane translocation) were determined by immunoblotting. Calcification medium induced osteogenic differentiation, reduced matrix Gla protein content, and increased expression of the sodium-dependent cotransporter Pit-1. Magnesium prevented calcification and decreased osteocalcin expression and BMP-2 activity and increased expression of calcification inhibitors, osteopontin and matrix Gla protein. TRPM 7 activation was decreased by calcification medium, an effect reversed by magnesium. 2-APB recapitulated the VSMC osteoblastic phenotype in VSMCs. Osteocalcin was increased by calcification medium in VSMCs and intact vessels from MgL but not MgH, whereas osteopontin was increased in MgH, but not in MgL mice. Magnesium negatively regulates vascular calcification and osteogenic differentiation through increased/restored TRPM7 activity and increased expression of anticalcification proteins, including osteopontin, BMP-7, and matrix Gla protein. New molecular insights are provided whereby magnesium could protect against VSMC calcification.

Original languageEnglish (US)
Pages (from-to)453-462
Number of pages10
JournalHypertension
Volume56
Issue number3
DOIs
StatePublished - Sep 2010
Externally publishedYes

Keywords

  • BMP
  • calcification
  • chronic kidney disease
  • hypertension
  • osteocalcin
  • osteopontin
  • vessels

ASJC Scopus subject areas

  • Internal Medicine

Fingerprint

Dive into the research topics of 'Vascular smooth muscle cell differentiation to an osteogenic phenotype involves TRPM7 modulation by magnesium'. Together they form a unique fingerprint.

Cite this