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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL062329-13
Application #
8402645
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Srinivas, Pothur R
Project Start
1999-04-01
Project End
2014-12-31
Budget Start
2013-01-01
Budget End
2014-12-31
Support Year
13
Fiscal Year
2013
Total Cost
$371,280
Indirect Cost
$133,280
Name
University of Washington
Department
Biomedical Engineering
Type
Schools of Engineering
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Paloian, Neil J; Leaf, Elizabeth M; Giachelli, Cecilia M (2016) Osteopontin protects against high phosphate-induced nephrocalcinosis and vascular calcification. Kidney Int 89:1027-36
Yamada, Shunsuke; Giachelli, Cecilia M (2016) Vascular calcification in CKD-MBD: Roles for phosphate, FGF23, and Klotho. Bone :
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 lamininα1 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
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
Paloian, Neil J; Giachelli, Cecilia M (2014) A current understanding of vascular calcification in CKD. Am J Physiol Renal Physiol 307:F891-900
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
Wu, Meiting; Rementer, Cameron; Giachelli, Cecilia M (2013) Vascular calcification: an update on mechanisms and challenges in treatment. Calcif Tissue Int 93:365-73
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

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