The emerging role of phosphate in vascular calcification

Abstract

Vascular calcification is recognized as a major contributor to cardiovascular disease (CVD) in end stage renal disease (ESRD) patients. Susceptibility to vascular calcification is genetically determined and actively regulated by diverse inducers and inhibitors. One of these inducers, hyperphosphatemia, promotes vascular calcification and is a nontraditional risk factor for CVD mortality in ESRD patients. Vascular smooth muscle cells (SMCs) respond to elevated phosphate levels by undergoing an osteochondrogenic phenotype change and mineralizing their extracellular matrix through a mechanism requiring sodium-dependent phosphate cotransporters. Disease states and cytokines can increase expression of sodium-dependent phosphate cotransporters in SMCs, thereby increasing susceptibility to calcification even at phosphate concentrations that are in the normal range.

Fig. 1

Major Theories of Vascular Calcification Six different mechanisms that have been proposed to regulate the initiation or progression of vascular calcification are illustrated, along with key molecular mediators where known. The extent to which each of these mechanisms plays a role in vascular calcification in various disease states, including hyperphosphatemia and ESRD, is currently unknown.

Fig. 2

Proposed Role of Elevated Phosphate (Pi) in Osteochondrogenic Phenotype Change and Matrix Mineralization in Vascular SMC. Pi enters the cell through the sodium dependent phosphate cotransporters, Pit-1, and induces an osteochondrogenic phenotype change. This stimulates matrix vesicle calcium and Pi loading, as well as matrix changes that promote calcification. Molecules involved in regulating Pi loading of matrix vesicles or Pi efflux are currently unknown.