Smooth muscle cell-specific matrix metalloproteinase 3 deletion reduces osteogenic transformation and medial artery calcification.

AIMS: Vascular calcification is highly prevalent in atherosclerosis, diabetes, and chronic kidney disease. It is associated with increased morbidity and mortality in patients with cardiovascular disease. Matrix metalloproteinase 3 (MMP-3), also known as stromelysin-1, is part of the large matrix metalloproteinase family. It can degrade extracellular matrix components of the arterial wall including elastin, which plays a central role in medial calcification. In this study, we sought to determine the role of MMP-3 in medial calcification. METHODS AND RESULTS: We found that MMP-3 was increased in rodent models of medial calcification as well as in vascular smooth muscle cells (SMCs) cultured in a phosphate calcification medium. It was also highly expressed in calcified tibial arteries in patients with peripheral arterial disease (PAD). Knockdown and inhibition of MMP-3 suppressed phosphate-induced SMC osteogenic transformation and calcification, whereas the addition of a recombinant MMP-3 protein facilitated SMC calcification. In an ex vivo organ culture model and a rodent model of medial calcification induced by vitamin D3, we found that MMP-3 deficiency significantly suppressed medial calcification in the aorta. We further found that medial calcification and osteogenic transformation were significantly reduced in SMC-specific MMP-3-deficient mice, suggesting that MMP-3 in SMCs is an important factor in this process. CONCLUSION: These findings suggest that MMP-3 expression in vascular SMCs is an important regulator of medial calcification and that targeting MMP-3 could provide a therapeutic strategy to reduce it and address its consequences in patients with PAD.

An ultrasound-based femoral artery calcification score.

Objective: Duplex ultrasound (US) of the lower extremities is commonly used to assess patients with lower extremity atherosclerosis. Arterial calcification can often be visualized in these images; however, efforts to quantify its extent have been limited. We, thus, sought to develop a new scoring system to measure calcification on duplex US studies of the femoral artery and correlate it with standard computed tomography (CT)-based methods. We then made preliminary attempts to correlate US-based femoral artery calcification scores with limb-specific outcomes in patients with peripheral arterial disease. Methods: Patients who underwent CT evaluation of the lower extremities and arterial duplex US of either lower extremity within 6 months of each examination were included in the study. CT-based calcium scores of the femoral artery were generated using calcium scoring software. To determine the US score, five standard arterial segments (ie, common femoral artery, proximal superficial femoral artery [SFA], mid-SFA, distal SFA, and above the knee popliteal artery) were scored using a scale of 0 to 2 (0, a completely normal vessel segment; 1, a vessel with hyperechoic irregularities of the vessel wall; and 2, clear anechoic shadowing). The available scores were then averaged to yield a single femoral calcium score for each leg. Predictors of femoral calcification scores were then assessed and compared with the CT-based methods. The correlation between the US- and CT-based femoral calcification was assessed, and then the association between the US-based femoral calcification score and limb outcomes was evaluated. Results: A total of 113 patients met the inclusion criteria and were included in the final analysis. US-based calcification scores were increased in patients with diabetes, renal failure, and the presence of chronic limb threatening ischemia similar to CT-based femoral calcification. The US- and CT-based calcification scores showed a moderate to strong correlation (r = 0.64). An elevated US-based femoral artery calcification score was associated with decreased amputation-free survival. Conclusions: A novel US-based method shows promise as a simple method for quantifying the extent of femoral artery calcification in patients with peripheral arterial disease. The US-based method correlates with standard CT-based methods. Preliminary studies show that it could be useful for predicating outcomes for patients with peripheral arterial disease.