Mechanism of atherosclerotic calcification

Abstract

Calcification is almost invariably associated with atherosclerotic plaque lesions. Recent data suggest that plaque calcification is an active, regulated process similar to osteogenesis. In order to clarify the mechanism of plaque calcification, we developed an in vitro model of vascular calcification by utilizing bovine vascular smooth muscle cells (BVSMCs). This model is useful in that diffuse and massive calcification can be induced within 2 weeks and thereby biochemical analyses of vascular calcification can be performed. We have analyzed several aspects of vascular calcification by using this model and demonstrated as follows: 1) in vitro calcification of BVSMCs is regulated by calciotropic hormones and BVSMCs are equipped with a unique autocrine and/or paracrine system regulating calcium metabolism. 2) Sodium-dependent phosphate cotransport plays a crucial role in BVSMC calcification as well as in mineralization of skeletal tissues. 3) BVSMCs acquire osteoblastic phenotype under certain conditions. Finally, we discuss the roles of macrophages in the development of atherosclerotic calcification. Interferon-gamma (IFN-gamma) induces gene expression of 25-hydrovitamin D-1 alpha-hydroxylase (1 alpha OHase) and its activity in macrophages. Since 1 alpha OHase can locally convert 25-hydroxyvitamin D into 1 alpha, 25-dihydroxyvitamin D (1,25(OH)2D), an active metabolite of vitamin D, it is suggested that local production of 1,25(OH)2D by macrophages may promote atherosclerotic calcification. Moreover, macrophages may be involved in the phenotypic changes of vascular smooth muscle cells (VSMCs) to acquire calcifying capacity. Therefore, the phenotypic changes of VSMCs in atherosclerotic plaque may contribute to the development of atherosclerotic calcification.

Bone alkaline phosphatase isoforms in chronic kidney disease : mineral and bone disorder

“…Vascular calcification involves transdifferentiation of VSMCs to an osteoblast-like phenotype, which demonstrates increased expression of BALP (163). In study II we found that BALP isoforms B/I, B1x and B2 are involved in the calcification of VSMCs in vitro (258).…”

“…Furthermore ALP had been identified as an independent predictor of mortality in CKD and in the general population (171,174). Experimental studies demonstrated an association of ALP or BALP with vascular calcification (119,161,163) and the suppression of VSMC calcification through inhibition of ALP (233). A possible connection between this new putative origin of B1x in serum and our earlier hypothesis of an association with low bone turnover was provided by London et al…”

“…To test this hypothesis we cultured HASMCs in calcification medium containing β-glycerophosphate at concentrations of 5 or 10 mmol/L and calcium at a concentration of 2 mmol/l, with or without the specific ALP inhibitor tetramisole (161,242). We chose β-glycerophosphate as a phosphate donor, since it has been shown to consistently induce ALP when used as a component of calcification medium for VSMCs (148,149,161,163,242,243). Other phosphate donors have had stimulatory (244,245), absent (164), or even inhibitory (246) effects on ALP activity in calcifying VSMCs.…”

“…al. (163) and to identify the ALP isoforms expressed in calcifying human VSMCs with our HPLC based method, which, in contrast to immunological methods, is free from crossreactivity with other ALP isoforms (1). Based on our findings in study I of an association of elevated serum phosphate and calcium × phosphate product with the appearance of B1x in serum, we hypothesized that B1x is associated with the calcification of VSMCs (241).…”

Ultrastructure of Apatite Crystals Formed During Vascular Calcification in Humans

“…The causes and mechanisms of ectopic calcification, however, have not been fully elucidated as yet. As a result, pathological calcification, such as vascular calcification and fibrodysplasia ossificans progressiva, may be regulated by many possible contributing factors, and may occur in the same manner as bone calcification occurs after the conversion of soft tissue to hard tissue-forming cells, namely, osteoblasts or osteoblast-like cells [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] . Thus, mainly on the basis of in vitro results, differentiation of soft tissue into hard tissueforming cells is considered to be the primary cause of ectopic calcification.…”