PROJECT SUMMARY/ABSTRACT Vascular calcification, especially coronary artery calcification (CAC), is associated with increased risk of cardiovascular disease, whereas regular physical activity is associated with decreased risk. Thus, one would predict that physically active individuals would have less CAC, yet clinical studies show the opposite. Elite athletes actually have more CAC than their sedentary counterparts even though they have lower cardiac event rates. The objective of this proposal is to determine the mechanism of this paradox. As clinical studies show that coronary plaques containing large, contiguous calcium deposits are associated with less cardiovascular risk than fragmented calcium deposits, one possibility would be that exercise remodels calcium deposits into a more stable microarchitecture. Theoretical analytical modeling also predicts that decreased surface area of calcium deposits is expected to reduce plaque rupture risk. Interestingly, a single bout of exercise in humans and mice causes a transient 1.8-fold elevation of parathyroid hormone (PTH), and intermittent treatment of PTH in humans and mice causes increased bone growth, which shares signaling mechanisms with vascular calcification. Our recent findings provide an association between PTH and microarchitecture of vascular calcium deposits, where intermittent PTH treatment reduces the surface area of aortic calcium deposits in hyperlipidemic mice with pre-existing vascular calcification. Our preliminary studies provide a more direct association of exercise with the remodeling of vascular calcium deposits. We found that hyperlipidemic mice with pre-existing aortic calcification on a 9-week treadmill regimen had increased serum PTH levels, increased PTH receptor levels in the aortic roots, and decreased mineral surface area by nuclear imaging and histomorphometry. Thus, we hypothesize that exercise, through activation of the vascular PTH1 receptor, shifts the microarchitecture of calcium deposits toward a more stabilized form, reducing the rupture risk. We will test our hypothesis using 3 Specific Aims to determine: 1) whether loss of PTH1 receptor activation blocks the exercise-induced remodeling of vascular calcium deposits; 2) the relative contributions of circulating PTH and local (tissue) PTH related peptide (PTHrP) on the exercise-induced changes in microarchitecture; and 3) effects of confounding factors (sex, exercise dose, diet, and species) on exercise-induced changes in the SMC transcriptome and vascular calcium deposit microarchitecture. We will use pharmacologic, genetic, and surgical models, and the endpoints will include progression and microarchitecture of aortic calcium deposits, including size and surface area based on structural analyses (serial 18F-µPET/µCT, histomorphometry), transcriptome analysis, and functional biomechanical analyses using a balloon catheter as a mechanical sensor for rupture vulnerability. The proposed research is significant beca...