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VC is never benign; the presence and severity of VC correlate closely with the risk of myocardial events and cardiovascular mortality in multiple at\u2010risk populations such as patients with diabetes and chronic kidney disease. Mitochondrial dysfunction involving each of vascular wall constituents (endothelia and vascular smooth muscle cells (VSMCs)) aggravates various vascular pathologies, including atherosclerosis and VC. However, few studies address the pathogenic role of mitochondrial dysfunction during the course of VC, and mitochondrial reactive oxygen species (ROS) seem to lie in the pathophysiologic epicenter. Superoxide dismutase 2 (SOD2), through its preferential localization to the mitochondria, stands at the forefront against mitochondrial ROS in VSMCs and thus potentially modifies the probability of VC initiation or progression. In this review, we will provide a literature\u2010based summary regarding the relationship between SOD2 and VC in the context of VSMCs. Apart from the conventional wisdom of attenuating mitochondrial ROS, SOD2 has been found to affect mitophagy and the formation of the autophagosome, suppress JAK\/STAT as well as PI<jats:sub>3<\/jats:sub>K\/Akt signaling, and retard vascular senescence, all of which underlie the beneficial influences on VC exerted by SOD2. More importantly, we outline the therapeutic potential of a novel SOD2\u2010targeted strategy for the treatment of VC, including an ever\u2010expanding list of pharmaceuticals and natural compounds. It is expected that VSMC SOD2 will become an important druggable target for treating VC in the future.<\/jats:p>","DOI":"10.1155\/2021\/6675548","type":"journal-article","created":{"date-parts":[[2021,2,26]],"date-time":"2021-02-26T23:35:18Z","timestamp":1614382518000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":46,"title":["Superoxide Dismutase 2 (SOD2) in Vascular Calcification: A Focus on Vascular Smooth Muscle Cells, Calcification Pathogenesis, and Therapeutic 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