Roles and Regulation of Extracellular Vesicles in Cardiovascular Mineral Metabolism

Cardiovascular calcification is a multifaceted disease that is a leading independent predictor of cardiovascular morbidity and mortality. Recent studies have identified a calcification-prone population of extracellular vesicles as the putative elementary units of vascular microcalcification in diseased heart valves and vessels. Their action is highly context-dependent; extracellular vesicles released by smooth muscle cells, valvular interstitial cells, endothelial cells, and macrophages may promote or inhibit mineralization, depending on the phenotype of their originating cells and/or the extracellular environment to which they are released. In particular, emerging roles for vesicular microRNAs, bioactive lipids, metabolites, and protein cargoes in driving this pro-calcific switch underpin the necessity of innovative strategies to employ next-generation sequencing and omics technologies in order to better understand the pathobiology of these nano-sized entities. Furthermore, a recent body of work has emerged that centers on the novel re-purposing of extracellular vesicles and exosomes as potential therapeutic avenues for cardiovascular calcification. This review aims to highlight the role of extracellular vesicles as constituents of cardiovascular calcification and summarizes recent advances in our understanding of the biophysical nature of vesicle accumulation, aggregation, and mineralization. We also comprehensively discuss the latest evidence that extracellular vesicles act as key mediators and regulators of cell/cell communication, osteoblastic/osteoclastic differentiation, and cell/matrix interactions in cardiovascular tissues. Lastly, we highlight the importance of robust vesicle isolation and characterization when studying these phenomena, and offer a brief primer on working with cardiovascular applications of extracellular vesicles.