Abstract-Vascular calcification, long thought to result from passive degeneration, involves a complex, regulated process of biomineralization resembling osteogenesis. Evidence indicates that proteins controlling bone mineralization are also involved in the regulation of vascular calcification. Artery wall cells grown in culture are induced to become osteogenic by inflammatory and atherogenic stimuli. Furthermore, osteoclast-like cells are found in calcified atherosclerotic plaques, and active resorption of ectopic vascular calcification has been demonstrated. In general, soft tissue calcification arises in areas of chronic inflammation, possibly functioning as a barrier limiting the spread of the inflammatory stimulus. Atherosclerotic calcification may be one example of this process, in which oxidized lipids are the inflammatory stimulus. Calcification is widely used as a clinical indicator of atherosclerosis. It progresses nonlinearly with time, following a sigmoid-shaped curve. The relationship between calcification and clinical events likely relates to mechanical instability introduced by calcified plaque at its interface with softer, noncalcified plaque. In general, as calcification proceeds, interface surface area increases initially, but eventually decreases as plaques coalesce. Key Words: calcification Ⅲ atherosclerosis Ⅲ inflammation Ⅲ bone Ⅲ vascular V ascular calcification is an important manifestation of atherosclerosis. For more than half a century, it has been associated with a poor prognosis attributable to vascular disease. 1 Its presence is a strong indicator of chronic inflammatory disease, usually atherosclerosis, and its extent directly relates to the overall burden of atherosclerotic disease. 2 Despite its clinical relevance, research on the mechanism of mineral deposition in arteries has been limited and remains at an early scientific stage relative to research on other aspects of atherosclerosis, such as lipoprotein biochemistry and inflammation. Mechanisms of Vascular CalcificationVascular calcification recapitulates embryonic osteogenesis. Pathologists in the 19th century recognized the presence of bone-like tissue within atherosclerotic arteries, with lamellar structure, osteoblast-like cells, and hematopoietic elements. 3 Yet, for most of the 20th century, vascular calcification has been regarded as a passive, unregulated, degenerative process occurring within advanced atherosclerotic plaques. The concept of regulated ossification as the mechanism behind vascular calcification has re-emerged only in the past decade. 4,5 Ossification has been identified histologically in 60% of restenotic aortic valves after balloon valvuloplasty. 6 Approximately 15% of carotid atherosclerotic plaque specimens 7 and calcified cardiac valve tissue 8 have ossification. Vascular calcification may include both osteogenic and chondrogenic differentiation. In humans, it is primarily osteogenic with bone tissue formation, whereas in mice, it is primarily chondrogenic with cartilage formation. Although osteoblas...

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Abstract-The presence of ectopic tissue in the diseased artery wall is evidence for the presence of multipotential stem cells in the vasculature. Mesenchymal stem cells were first identified in the marrow stroma, and they differentiate along multiple lineages giving rise to cartilage, bone, fat, muscle, and vascular tissue in vitro and in vivo. Transplantation studies show that marrow-derived mesenchymal stem cells appear to enter the circulation and engraft other tissues, including the artery wall, at sites of injury. Recent evidence indicates that mesenchymal stem cells are also present in normal artery wall and microvessels and that they also may enter the circulation, contributing to the population of circulating progenitor cells and engrafting other tissues. Thus, the artery wall is not only a destination but also a source of progenitor cells that have regenerative potential. Although potential artifacts, such as fusion, need to be taken into consideration,

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Fish oil supplementation is associated with lower risk of coronary artery disease in humans, and it has been shown to reduce ectopic calcification in an animal model. However, whether N-3 fatty acids, active ingredients of fish oil, have direct effects on calcification of vascular cells is not clear. In this report, we investigated the effects of eicosapentaenoic acid and docosahexaenoic acid (DHA) on osteoblastic differentiation and mineralization of calcifying vascular cells (CVCs), a subpopulation of bovine aortic medial cells that undergo osteoblastic differentiation and form calcified matrix in vitro. Results showed that N-3 fatty acids inhibited alkaline phosphatase (ALP) activity and mineralization of vascular cells, suggesting that they directly affect osteoblastic differentiation in vascular cells. By Western blot analysis, DHA activated p38-mitogen-activated protein kinase (MAPK) but not extracellular-regulated kinase (ERK) or Akt. An inhibitor of p38-MAPK partially reversed the inhibitory effects of DHA on osteoblastic differentiation and mineralization. Transient transfection experiments showed that DHA also activated peroxisome proliferator-activated receptor-␥ (PPAR-␥). Both p38-MAPK activator and PPAR-␥ agonists reproduced the inhibitory effects of DHA on CVC mineralization. Pretreatment with DHA also inhibited interleukin-6 -induced ALP activity and mineralization. Together, these results suggest that N-3 fatty acids directly inhibit vascular calcification, and that the inhibitory effects are mediated by the p38-MAPK and PPAR-␥ pathways.V ascular calcification, a clinically significant pathological process similar to endochondral osteogenesis, 1 is positively regulated by developmental factors such as bone morphogentic protein-2 (BMP-2), Msx-2, and Wnt and negatively regulated by other factors such as osteopontin, matrix gamma-carboxyglutamic acid (GLA) protein, and nucleotide pyrophosphate/phosphodiesterase-1. 1,2 Vascular calcification develops in parallel with atherosclerosis and is stimulated by inflammatory cytokines and lipid oxidation products. 2 Fish oil consumption associates with reduced atherosclerosis. 3 Its active ingredients, N-3 fatty acids, cis-5,8,11,14,17-eicosapentaenoic acid (EPA; C20:5n-3) and cis-4,7,10,13,16,19-docosahexaenoic acid (DHA; C22:6n-3), are potent antiinflammatory peroxisome proliferator-activated receptor-␥ (PPAR-␥) agonists. 4 -5 N-3 fatty acid supplementation also reduces ectopic calcification in vivo. 6 -7 However, it is not known whether the effects are direct.Several investigators identified vascular cells with osteogenic potential, 8 -10 including calcifying vascular cells (CVCs), which undergo osteoblastic differentiation and mineralization. [11][12] In this study, we investigated whether N-3 fatty acids directly inhibit osteoblastic differentiation of CVCs. Results show that they inhibit both spontaneous and interleukin-6 (IL-6)-induced osteoblastic differentiation in these vascular cells, and that the effects are mediated by the p38-mitogen-activated ...