Vascular Calcification

Macrovascular calcification increasingly afflicts our aging and dysmetabolic population.1 Once considered only a passive process of dead and dying cells, data from multiple laboratories worldwide have converged to reveal that vascular calcification is in great part an actively regulated form of matrix mineral metabolism.2 A uniquely horrendous situation arises in end-stage renal disease.3 Antecedent vasculopathy from diabetes, dyslipidemia, or hypertension interacts with dialysis-modulated uremia—a fluctuating hyperphosphatemic and hyperphosphatemic milieu that increases vascular smooth muscle cell (VSMC) apoptosis, overwhelms defenses against soft tissue mineralization, and promotes low-grade panvascular inflammation.3,4 Elegant genetic studies by Cecil and Terkeltaub,5 coupled with the enlightening work of Festing et al6 and Li et al7 have highlighted the important role of pyrophosphate and phosphate metabolism in the pathobiology of arterial calcification. In addition, oxidative stress signals (reactive oxygen species [ROS]) elaborated in response to key inflammatory cytokines—namely, interleukin6,8 interleukin 1β,9 and tumor necrosis factor10,11—have been shown to participate in vascular activation of the osteochondrogenic gene programs characteristic of bone formation.12 Only recently, however, has signaling via the receptor for advanced glycosylation end products (RAGE) been implicated as a critical contributor to both ROS-regulated13 and pyrophosphate-regulated5 vascular calcification. RAGE is an …