Signaling pathways involved in vascular smooth muscle cell calcification during hyperphosphatemia

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.

Fig. 1

Role of vascular smooth muscle cells in vascular calcification. Following exposure to pro-calcific factors, most importantly hyperphosphatemia, vascular smooth muscle cells (VSMCs) are able to transdifferentiate into an osteo-/chondrogenic phenotype. This process is characterized and, at least partly, mediated by expression of osteogenic transcription factors such as CBFA1, MSX2, SOX9, and osterix. The osteo-/chondroblast-like cells actively promote calcification by reduced availability of calcification inhibitors, apoptosis, and apoptotic body release as well as release of calcifying extracellular vesicles, remodeling of the extracellular matrix and elastin degradation, and a pro-inflammatory state with release of pro-inflammatory cytokines and oxidative stress. These create a pro-calcifying environment, which allows for active mineralization of the vasculature

Fig. 2

Critical signaling pathways involved in osteo-/chondrogenic transdifferentiation of vascular smooth muscle cells. Simplified schematic illustration of important phosphate-induced signaling pathways discussed in this review, ultimately leading to osteo-chondrogenic transdifferentiation of vascular smooth muscle cells (VSMCs), development of a pro-calcifying environment, and vascular calcification. For details and abbreviations, see the full text