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• W2096173285 abstract "Vascular calcification is a multifaceted process involving gain of calcification inducers and loss of calcification inhibitors. One such inhibitor is inorganic pyrophosphate (PP i ), and regulated generation and homeostasis of extracellular PP i is a critical determinant of soft-tissue mineralization. We recently described an autocrine mechanism of extracellular PP i generation in cultured rat aortic vascular smooth muscle cells (VSMC) that involves both ATP release coupled to the ectophosphodiesterase/pyrophosphatase ENPP1 and efflux of intracellular PP i mediated or regulated by the plasma membrane protein ANK. We now report that increased cAMP signaling and elevated extracellular inorganic phosphate (P i ) act synergistically to induce calcification of these VSMC that is correlated with progressive reduction in ability to accumulate extracellular PP i . Attenuated PP i accumulation was mediated in part by cAMP-dependent decrease in ANK expression coordinated with cAMP-dependent increase in expression of TNAP, the tissue nonselective alkaline phosphatase that degrades PP i . Stimulation of cAMP signaling did not alter ATP release or ENPP1 expression, and the cAMP-induced changes in ANK and TNAP expression were not sufficient to induce calcification. Elevated extracellular P i alone elicited only minor calcification and no significant changes in ANK, TNAP, or ENPP1. In contrast, combined with a cAMP stimulus, elevated P i induced decreases in the ATP release pathway(s) that supports ENPP1 activity; this resulted in markedly reduced rates of PP i accumulation that facilitated robust calcification. Calcified VSMC were characterized by maintained expression of multiple SMC differentiation marker proteins including smooth muscle (SM) α-actin, SM22α, and calponin. Notably, addition of exogenous ATP (or PP i per se) rescued cAMP + phosphate-treated VSMC cultures from progression to the calcified state. These observations support a model in which extracellular PP i generation mediated by both ANK- and ATP release-dependent mechanisms serves as a critical regulator of VSMC calcification." @default.
• W2096173285 created "2016-06-24" @default.
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• W2096173285 date "2010-03-01" @default.
• W2096173285 modified "2023-09-24" @default.
• W2096173285 title "Regulation of vascular smooth muscle cell calcification by extracellular pyrophosphate homeostasis: synergistic modulation by cyclic AMP and hyperphosphatemia" @default.
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• W2096173285 doi "https://doi.org/10.1152/ajpcell.00419.2009" @default.
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