Phosphate Regulation of Vascular Smooth Muscle Cell Calcification

Abstract

Vascular calcification is a common finding in atherosclerosis and a serious problem in diabetic and uremic patients. Because of the correlation of hyperphosphatemia and vascular calcification, the ability of extracellular inorganic phosphate levels to regulate human aortic smooth muscle cell (HSMC) culture mineralization in vitro was examined. HSMCs cultured in media containing normal physiological levels of inorganic phosphate (1.4 mmol/L) did not mineralize. In contrast, HSMCs cultured in media containing phosphate levels comparable to those seen in hyperphosphatemic individuals (>1.4 mmol/L) showed dose-dependent increases in mineral deposition. Mechanistic studies revealed that elevated phosphate treatment of HSMCs also enhanced the expression of the osteoblastic differentiation markers osteocalcin and Cbfa-1. The effects of elevated phosphate on HSMCs were mediated by a sodium-dependent phosphate cotransporter (NPC), as indicated by the ability of the specific NPC inhibitor phosphonoformic acid, to dose dependently inhibit phosphate-induced calcium deposition as well as osteocalcin and Cbfa-1 gene expression. With the use of polymerase chain reaction and Northern blot analyses, the NPC in HSMCs was identified as Pit-1 (Glvr-1), a member of the novel type III NPCs. These data suggest that elevated phosphate may directly stimulate HSMCs to undergo phenotypic changes that predispose to calcification and offer a novel explanation of the phenomenon of vascular calcification under hyperphosphatemic conditions. The full text of this article is available at http://www.circresaha.org.

Insulin attenuates vascular smooth muscle calcification but increases vascular smooth muscle cell phosphate transport

“…The mechanisms for vascular calcification in these clinical settings are still being elucidated (5,6), but increased vascular calcification is clearly associated with hyperphosphatemia (7) and with increased serum calcium-phosphate ion product.…”

High-phosphate-induced calcification is related to SM22α promoter methylation in vascular smooth muscle cells

“…(1,(5)(6)(7)(8)(12)(13)(14)(15)(16)(17)(18) Our results are the first to relate DNA methylation with the loss of smooth muscle lineage marker SM22a in VSMCs incubated with high phosphate. SM22a promoter methylation decreases SM22a gene expression, and this fact could facilitate phenotypic transition of VSMCs to osteoblast-like cell.…”

Acute tumoral calcinosis due to severe hyperphosphatemia in a maintenance hemodialysis patient

“…Continued hyperphosphatemia could stimulate transformation of the arteriolar medial vascular smooth muscle cells into osteoblasts, which may be the mechanism underlying Mönkeberg's medial calcification. This process has been demonstrated in vitro using human vascular smooth muscle cells (VSMCs) and in vivo in mice [9]. Similarly, bone mineral deposition also occurs in the media of the peripheral artery in humans, where human VSMCs then develop osteoblast characteristics [10].…”