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
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United States
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Yamada, Shunsuke; Leaf, Elizabeth M; Chia, Jia Jun et al. (2018) PiT-2, a type III sodium-dependent phosphate transporter, protects against vascular calcification in mice with chronic kidney disease fed a high-phosphate diet. Kidney Int 94:716-727
Yamada, Shunsuke; Wallingford, Mary C; Borgeia, Suhaib et al. (2018) Loss of PiT-2 results in abnormal bone development and decreased bone mineral density and length in mice. Biochem Biophys Res Commun 495:553-559
Scatena, Marta; Jackson, Melissa F; Speer, Mei Y et al. (2018) Increased Calcific Aortic Valve Disease in response to a diabetogenic, procalcific diet in the LDLr-/-ApoB100/100 mouse model. Cardiovasc Pathol 34:28-37
Yamada, Shunsuke; Giachelli, Cecilia M (2017) Vascular calcification in CKD-MBD: Roles for phosphate, FGF23, and Klotho. Bone 100:87-93
Giachelli, Cecilia M; Speer, Mei Y (2017) Noncanonical Wnts at the Cusp of Fibrocalcific Signaling Processes in Human Calcific Aortic Valve Disease. Arterioscler Thromb Vasc Biol 37:387-388
Wallingford, Mary Catherine; Chia, Jia Jun; Leaf, Elizabeth M et al. (2017) SLC20A2 Deficiency in Mice Leads to Elevated Phosphate Levels in Cerbrospinal Fluid and Glymphatic Pathway-Associated Arteriolar Calcification, and Recapitulates Human Idiopathic Basal Ganglia Calcification. Brain Pathol 27:64-76
Paloian, Neil J; Leaf, Elizabeth M; Giachelli, Cecilia M (2016) Osteopontin protects against high phosphate-induced nephrocalcinosis and vascular calcification. Kidney Int 89:1027-1036
Wallingford, Mary C; Gammill, Hilary S; Giachelli, Cecilia M (2016) Slc20a2 deficiency results in fetal growth restriction and placental calcification associated with thickened basement membranes and novel CD13 and laminin?1 expressing cells. Reprod Biol 16:13-26
Lin, Mu-En; Chen, Theodore; Leaf, Elizabeth M et al. (2015) Runx2 Expression in Smooth Muscle Cells Is Required for Arterial Medial Calcification in Mice. Am J Pathol 185:1958-69
Chavkin, Nicholas W; Chia, Jia Jun; Crouthamel, Matthew H et al. (2015) Phosphate uptake-independent signaling functions of the type III sodium-dependent phosphate transporter, PiT-1, in vascular smooth muscle cells. Exp Cell Res 333:39-48

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