{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T22:56:48Z","timestamp":1768517808596,"version":"3.49.0"},"reference-count":53,"publisher":"American Physiological Society","issue":"3","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Cell Physiology"],"published-print":{"date-parts":[[2010,3]]},"abstract":"<jats:p> Vascular calcification is a multifaceted process involving gain of calcification inducers and loss of calcification inhibitors. One such inhibitor is inorganic pyrophosphate (PP<jats:sub>i<\/jats:sub>), and regulated generation and homeostasis of extracellular PP<jats:sub>i<\/jats:sub> is a critical determinant of soft-tissue mineralization. We recently described an autocrine mechanism of extracellular PP<jats:sub>i<\/jats:sub> 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<jats:sub>i<\/jats:sub> mediated or regulated by the plasma membrane protein ANK. We now report that increased cAMP signaling and elevated extracellular inorganic phosphate (P<jats:sub>i<\/jats:sub>) act synergistically to induce calcification of these VSMC that is correlated with progressive reduction in ability to accumulate extracellular PP<jats:sub>i<\/jats:sub>. Attenuated PP<jats:sub>i<\/jats:sub> 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<jats:sub>i<\/jats:sub>. 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<jats:sub>i<\/jats:sub> alone elicited only minor calcification and no significant changes in ANK, TNAP, or ENPP1. In contrast, combined with a cAMP stimulus, elevated P<jats:sub>i<\/jats:sub> induced decreases in the ATP release pathway(s) that supports ENPP1 activity; this resulted in markedly reduced rates of PP<jats:sub>i<\/jats:sub> accumulation that facilitated robust calcification. Calcified VSMC were characterized by maintained expression of multiple SMC differentiation marker proteins including smooth muscle (SM) \u03b1-actin, SM22\u03b1, and calponin. Notably, addition of exogenous ATP (or PP<jats:sub>i<\/jats:sub> per se) rescued cAMP + phosphate-treated VSMC cultures from progression to the calcified state. These observations support a model in which extracellular PP<jats:sub>i<\/jats:sub> generation mediated by both ANK- and ATP release-dependent mechanisms serves as a critical regulator of VSMC calcification. <\/jats:p>","DOI":"10.1152\/ajpcell.00419.2009","type":"journal-article","created":{"date-parts":[[2009,12,17]],"date-time":"2009-12-17T05:36:08Z","timestamp":1261028168000},"page":"C702-C713","source":"Crossref","is-referenced-by-count":61,"title":["Regulation of vascular smooth muscle cell calcification by extracellular pyrophosphate homeostasis: synergistic modulation by cyclic AMP and hyperphosphatemia"],"prefix":"10.1152","volume":"298","author":[{"given":"Domenick A.","family":"Prosdocimo","sequence":"first","affiliation":[{"name":"Department of Physiology and Biophysics, School of Medicine, Case Western Reserve University, Cleveland, Ohio; and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Steven C.","family":"Wyler","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics, School of Medicine, Case Western Reserve University, Cleveland, Ohio; and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrea M.","family":"Romani","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics, School of Medicine, Case Western Reserve University, Cleveland, Ohio; and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"W. 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