Mechanisms of Vascular Calcification

University Of Washington, Seattle WA

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Abstract

DESCRIPTION (provided by applicant): The long term objectives of the research are to delineate mechanisms of vascular calcification, especially those involved in arterial medial calcification that is prevalent in end stage renal disease (ESRD), in order to identify targets for prevention and treatment of this debilitating process. We have developed a phosphate-induced, uremic mouse model of arterial medial calcification that mimics the type and extent of calcification observed in ESRD patients. Preliminary data indicate that calcification in this model correlates with serum phosphate and osteopontin levels, and appears to involve smooth muscle cell phenotypic transformation, including Runx2 upregulation. The sodium dependent phosphate co-transporters, Pit-1 and Pit-2, are expressed in smooth muscle cells (SMCs), and during the previous funding period we discovered that Pit-1 was required for smooth muscle cell phenotype change and calcification in vitro. Furthermore, Pit-2 but not Pit-1, was found in SMC matrix vesicles, suggesting a potential role for this molecule in phosphate efflux. The aims of the current proposal are to 1) determine the mechanisms and functional outcomes of arterial medial calcification in uremic, phosphate fed mice on the calcification susceptible background, 2) determine the function of Pit-1 in vascular calcification in mouse models of arterial medial calcification, and 3) Determine the contribution of Pit-2 in matrix vesicles versus phosphate efflux to SMC mineralization in vitro.