Vascular calcification is an actively regulated process contributing to increased morbidity and mortality in, patients with uremia, diabetes, aortic stenosis and bioprosthetic heart valves. Epidemiological studies have linked vascular calcification with osteoporosis and cardiovascular disease, suggesting that common regulatory mechanisms exist, and that ectopic calcification may increase the risk of heart disease. In human blood vessels and valves, both diffuse calcification and ectopic bone have been observed under pathological conditions. The relationship between these types of mineralization is unclear. It is also unknown if media or intimal vascular calcification contributes to formation and/or progression of atherosclerotic lesions. We hypothesize that mineral deposition in blood vessels involves mediators including osteopontin (OPN), osteoprotegerin (OPG) and matrix gla proteins (MGP), that also critically control formation of the skeleton, and that once mineral forms in the vessel wall, an adaptive response ensues and initiates cellular differentiation and inflammatory mechanisms that 1) lead to neointima formation and hence increased susceptibility to plaque formation, and 2) mimic endochondral bone formation that may explain the appearance of ectopic bones in calcified vascular lesions. In order to identify common mechanisms! controlling bone and vascular calcification, and to understand the relationship between vascular calcification, cartilaginous metaplasia, and arterial lesion development, three aims are proposed.
Aim I will determine the mechanism of medial vascular calcification, neointimal formation, and cartilaginous metaplasia in MGP X OPN mutant mice.
Aim 2 will determine the mechanism of bone and tooth defects found in MGP X OPN mice.
Aim 3 will determine the effect of hyperlipidemia on cartilaginous metaplasia, vascular calcification and osteoporosis in a mouse model of atherosclerosis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR048798-04
Application #
6752878
Study Section
Special Emphasis Panel (ZHL1-CSR-O (S1))
Program Officer
Sharrock, William J
Project Start
2001-09-30
Project End
2006-05-31
Budget Start
2004-06-01
Budget End
2006-05-31
Support Year
4
Fiscal Year
2004
Total Cost
$270,720
Indirect Cost
Name
University of Washington
Department
Biomedical Engineering
Type
Schools of Engineering
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
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Giachelli, Cecilia M (2004) Vascular calcification mechanisms. J Am Soc Nephrol 15:2959-64
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