The emerging role of phosphate in vascular calcification

Abstract

Abstract/Summary 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.

The Risk for Medial Arterial Calcification in CKD

“…Whereas levels of parathyroid hormone and fibroblast growth factor 23 are elevated in stage 3 CKD, the prevalence of hyperphosphatemia is still low but increases sharply in stage 4 CKD, corresponding to the significant increase in BAC. This implicates hyperphosphatemia as opposed to the other abnormalities in the onset of MAC, a result consistent with a large body of experimental data indicating the pathogenic role of phosphate (9,10). However, this does not rule out a role for parathyroid hormone or fibroblast growth factor 23; confirmation of this possibility and whether the smaller increase in risk for MAC in stage 3 CKD is related to hyperphosphatemia will require future prospective studies directly correlating MAC with mineral metabolism.…”

Role of extracellular membrane vesicles in the pathogenesis of various diseases, including cancer, renal diseases, atherosclerosis, and arthritis

“…In Trousseau's syndrome, widespread thromboembolism becomes the dominant feature of the patient's cancer-related illness, and often serves as the cause of death. 68 Osteoarthritis Osteoarthritis (OA) is a progressive disease of unknown etiology characterized by degeneration of articular cartilage, particularly in large, weight-bearing joints (namely the knee Bobryshev et al, 18 Chen et al, 15 Demer and Tintut, 22 Giachelli, 21 Hsu and Camacho, 4 Kim, 19 Li et al, 20 Reynolds et al, 17 Shao et al, 23 Tanimura Amabile et al, 29 Bakouboula et al, 27 Chironi et al, 28 Dvorak, 30 Enjeti et al, 33 Satta et al 32 …”

Pathologic calcification of adult vascular smooth muscle cells differs on their crest or mesodermal embryonic origin

“…(9) On the other hand, the regions flanking both sides of the aortic arch region are of mesodermal origin. (10)(11)(12)(13) In this study we thus addressed our hypothesis by investigating the response of these distinct regions of the aorta to hyperphosphatemia, a classic stimulator of calcification, (2) by combining in vitro, ex vivo, and in vivo experiments using a mouse model deficient in matrix Gla protein (Mgp), (14) , a potent calcification inhibitor that develops extensive and spontaneous calcification of the media of the aorta. (14)(15)(16) …”

“…A large number of in vitro studies, together with observations made from genetically engineered mice that manifest calcifications in their vessel walls, now strongly supports the idea that vascular calcification is an active and highly regulated deposition of hydroxyapatite crystals-similar to those found in skeletal tissues-in the extracellular matrix (ECM) of vascular smooth muscle cells (VSMCs). (2,3) While very exceptionally present in veins, (4) vascular calcifica-as diverse as coronaries, distal arteries, and the aorta. Moreover, very interestingly, the location and degree of calcification very much depend on the underlying disorder.…”