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.

Public Health Relevance

Calcification of the blood vessels and valves is associated with a number of diseases including end stage renal disease, calcific valve disease, and cardiovascular disease that afflict millions of people world wide. Vascular calcification contributes to the high levels of morbidity and mortality seen in these patients. Our studies aim to determine mechanisms of vascular calcification such that new targets for therapeutic treatment can be identified.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
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Srinivas, Pothur R
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University of Washington
Biomedical Engineering
Schools of Engineering
United States
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Wallingford, Mary C; Giachelli, Cecilia M (2014) Loss of PiT-1 results in abnormal endocytosis in the yolk sac visceral endoderm. Mech Dev 133:189-202
Nguyen, Anh T; Gomez, Delphine; Bell, Robert D et al. (2013) Smooth muscle cell plasticity: fact or fiction? Circ Res 112:17-22
Crouthamel, Matthew H; Lau, Wei Ling; Leaf, Elizabeth M et al. (2013) Sodium-dependent phosphate cotransporters and phosphate-induced calcification of vascular smooth muscle cells: redundant roles for PiT-1 and PiT-2. Arterioscler Thromb Vasc Biol 33:2625-32
Lau, Wei Ling; Linnes, Michael; Chu, Emily Y et al. (2013) High phosphate feeding promotes mineral and bone abnormalities in mice with chronic kidney disease. Nephrol Dial Transplant 28:62-9
Scialla, Julia J; Lau, Wei Ling; Reilly, Muredach P et al. (2013) Fibroblast growth factor 23 is not associated with and does not induce arterial calcification. Kidney Int 83:1159-68
Wu, Meiting; Rementer, Cameron; Giachelli, Cecilia M (2013) Vascular calcification: an update on mechanisms and challenges in treatment. Calcif Tissue Int 93:365-73
Liu, Li; Sanchez-Bonilla, Marilyn; Crouthamel, Matthew et al. (2013) Mice lacking the sodium-dependent phosphate import protein, PiT1 (SLC20A1), have a severe defect in terminal erythroid differentiation and early B cell development. Exp Hematol 41:432-43.e7
Naik, Veena; Leaf, Elizabeth M; Hu, Jie Hong et al. (2012) Sources of cells that contribute to atherosclerotic intimal calcification: an in vivo genetic fate mapping study. Cardiovasc Res 94:545-54
Shanahan, Catherine M; Crouthamel, Matthew H; Kapustin, Alexander et al. (2011) Arterial calcification in chronic kidney disease: key roles for calcium and phosphate. Circ Res 109:697-711
Pai, Ashwini; Leaf, Elizabeth M; El-Abbadi, Mohga et al. (2011) Elastin degradation and vascular smooth muscle cell phenotype change precede cell loss and arterial medial calcification in a uremic mouse model of chronic kidney disease. Am J Pathol 178:764-73

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