Inflammation and the Osteogenic Regulation of Vascular Calcification

Abstract

A rterial biomineralization processes have been afflicting humans for Ն5 millennia, as realized in 2003 via the computed tomographic imaging of Ö tzi, the intriguing "ice mummy" discovered in the Tyrolean Alps. 1 Patchy abdominal atherosclerotic calcification was readily detected in the postmortem of this Ϸ40-year-old hunter of the early Copper Age, by 2000 years a predecessor of King Tutankhamen. 1 Today, an epidemic of vascular calcification is emerging within our aging and dysmetabolic populace. 2,3 Although vascular calcification was once considered only a passive process of dead and dying cells, work from laboratories worldwide has now highlighted that arterial biomineralization is an actively regulated form of calcified tissue metabolism. 4,5 Moreover, as in skeletal development -where unique biology controls matrix mineralization in membranous bone, endochondral bone, dentin, and enamel, 6,7 mechanistic diversity exists in the pathobiology of vascular calcium deposition. 2,4,5,8 Five common forms of vascular calcification, each possessing unique histoanatomic characteristics and clinical settings with overlapping yet distinct molecular mechanisms, have been described to date 4,5,9 (Table 1). Although we touch on the subject, the reader is referred to other contemporary reviews for in-depth consideration of pathogenic differences. 2,4,5 In this brief review and perspective, we recount recent data that emphasize inflammation and oxidative stress signaling as key contributors to the pathogenesis of vascular mineral deposition. 10 Furthermore, we highlight differences between the low-density lipoprotein receptor (LDLR)-deficient and apolipoprotein E (apoE)-deficient murine models ( Table 2) that help articulate the multifaceted contributions of dyslipidemia, diabetes mellitus, and uremia to arterial calcium deposition. 2,4,11 We end by summarizing the importance of considering these disease stage-and context-specific contributions arterial mineralization when crafting therapeutic strategies to address the disease burden of vascular calcification that increasingly afflicts our patients. 5 28 -32 In this section, we review this new data and also highlight distinctions between the LDLR Ϫ/Ϫ and apoE Ϫ/Ϫ murine disease models 33 ( Table 2) that provide insights into the mechanistic complexities of inflammation-dependent arterial calcium accumulation. RANKL and Atherosclerotic CalcificationReceptor Activator of Nuclear Factor B Ligand/ Osteoprotegerin Signaling and Atherosclerotic Calcification The first robust evidence for the primary contributions of inflammatory cytokine signaling to pathogenesis of vascular calcification arose from the generation and evaluation of the osteoprotegerin (OPG) Ϫ/Ϫ mouse. 34 OPG-deficient mice develop severe medial and intimal arterial calcification in conjunction with high-turnover osteoporosis driven by excessive osteoclast formation. 34 OPG was first shown to function as an antagonistic "faux receptor" of receptor activator of nuclear factor B ligand (RANKL), the TNF superfamil...

Notch ligand Delta-like 4 blockade attenuates atherosclerosis and metabolic disorders

“…S3C). Several studies, including ours, have shown that macrophages promote arterial calcification (27)(28)(29), and other evidence indirectly suggests that Notch signaling also regulates calcification (30). Ab treatment significantly decreased advanced calcification (von Kossa) and osteogenic activity (alkaline phosphatase activity, ALP) in atherosclerotic lesions (Fig.…”

Extracellular Fluid Excess Is Significantly Associated With Coronary Artery Calcification in Patients With Chronic Kidney Disease

“…Several experimental and clinical studies have reported that inflammatory biomarkers such as tumor necrosis factor‐α, IL‐6, vascular adhesion molecule‐1, macrophage, and thrombomodulin were systemically or locally increased in the presence of ECF excess 39, 40. ECF excess directly induces a phenotype change in VSCMs and indirectly induces oxidative stress, which increases the production of bone morphogenetic protein 2 and endothelial cell–derived microparticles in endothelial cells, thereby enhancing the osteogenic signal acting on VSMCs 41, 42, 43…”

Serum Alkaline Phosphatase Negatively Affects Endothelium-Dependent Vasodilation in Naïve Hypertensive Patients

“…ALP hydrolyzes pyrophosphate, a potent calcification inhibitor, thereby favoring calcium salts deposition at tissue level. 36,37 Inhibition of ALP activity was able to reduce calcifications in vascular smooth muscle cells in the NPP1 (ecto-nucleotide pyrophosphatase/phosphodiesterases-1) and ANK (ankyrin)-deficient mice, 38 an experimental model characterized by extensive aortic calcification. Thus, ALP may be an active player in human atherosclerosis, a hypothesis in line with observational We graphically reported the competitive interaction between serum phosphorus (below/above the median value) and alkaline phosphatase (ALP) levels.…”