Signaling pathways involved in vascular smooth muscle cell calcification during hyperphosphatemia

Cell Mol Life Sci. 2019 Jun;76(11):2077-2091. doi: 10.1007/s00018-019-03054-z. Epub 2019 Mar 18.

Abstract

Medial vascular calcification has emerged as a putative key factor contributing to the excessive cardiovascular mortality of patients with chronic kidney disease (CKD). Hyperphosphatemia is considered a decisive determinant of vascular calcification in CKD. A critical role in initiation and progression of vascular calcification during elevated phosphate conditions is attributed to vascular smooth muscle cells (VSMCs), which are able to change their phenotype into osteo-/chondroblasts-like cells. These transdifferentiated VSMCs actively promote calcification in the medial layer of the arteries by producing a local pro-calcifying environment as well as nidus sites for precipitation of calcium and phosphate and growth of calcium phosphate crystals. Elevated extracellular phosphate induces osteo-/chondrogenic transdifferentiation of VSMCs through complex intracellular signaling pathways, which are still incompletely understood. The present review addresses critical intracellular pathways controlling osteo-/chondrogenic transdifferentiation of VSMCs and, thus, vascular calcification during hyperphosphatemia. Elucidating these pathways holds a significant promise to open novel therapeutic opportunities counteracting the progression of vascular calcification in CKD.

Keywords: CKD; Osteogenic signaling; Phosphate; Vascular calcification; Vascular smooth muscle cells.

Publication types

  • Review

MeSH terms

  • Animals
  • Calcium Phosphates / chemistry
  • Calcium Phosphates / metabolism
  • Cell Transdifferentiation
  • Chondrocytes / metabolism
  • Chondrocytes / pathology
  • Gene Expression Regulation
  • Humans
  • Hyperphosphatemia / complications
  • Hyperphosphatemia / genetics
  • Hyperphosphatemia / metabolism*
  • Hyperphosphatemia / pathology
  • Muscle, Smooth, Vascular / metabolism*
  • Muscle, Smooth, Vascular / pathology
  • Myocytes, Smooth Muscle / metabolism*
  • Myocytes, Smooth Muscle / pathology
  • NF-kappa B / genetics
  • NF-kappa B / metabolism
  • Osteoblasts / metabolism
  • Osteoblasts / pathology
  • RANK Ligand / genetics
  • RANK Ligand / metabolism
  • Receptor Activator of Nuclear Factor-kappa B / genetics
  • Receptor Activator of Nuclear Factor-kappa B / metabolism
  • Renal Insufficiency, Chronic / complications
  • Renal Insufficiency, Chronic / genetics
  • Renal Insufficiency, Chronic / metabolism*
  • Renal Insufficiency, Chronic / pathology
  • Signal Transduction*
  • Vascular Calcification / complications
  • Vascular Calcification / genetics
  • Vascular Calcification / metabolism*
  • Vascular Calcification / pathology

Substances

  • Calcium Phosphates
  • NF-kappa B
  • RANK Ligand
  • Receptor Activator of Nuclear Factor-kappa B
  • TNFRSF11A protein, human
  • TNFSF11 protein, human