Editorial: Extracellular vesicles in cardiovascular inflammation and calcification

Clinical evidence links arterial calcification and cardiovascular risk. Finite-element modelling of the stress distribution within atherosclerotic plaques has suggested that subcellular microcalcifications in the fibrous cap may promote material failure of the plaque, but that large calcifications can stabilize it. Yet the physicochemical mechanisms underlying such mineral formation and growth in atheromata remain unknown. Here, by using three-dimensional collagen hydrogels that mimic structural features of the atherosclerotic fibrous cap, and high-resolution microscopic and spectroscopic analyses of both the hydrogels and of calcified human plaques, we demonstrate that calcific mineral formation and maturation results from a series of events involving the aggregation of calcifying extracellular vesicles, and the formation of microcalcifications and ultimately large calcification zones. We also show that calcification morphology and the plaque’s collagen content – two determinants of atherosclerotic plaque stability - are interlinked. Show more

Exosomes are small membrane-bound vesicles of endocytic origin that are actively secreted. The potential of exosomes as effective communicators of biological signaling in myocardial function has previously been investigated, and a recent explosion in exosome research not only underscores their significance in cardiac physiology and pathology, but also draws attention to methodological limitations of studying these extracellular vesicles. In this review, we discuss recent advances and challenges in exosome research with an emphasis on scientific innovations in isolation, identification, and characterization methodologies, and we provide a comprehensive summary of web-based resources available in the field. Importantly, we focus on the biology and function of exosomes, highlighting their fundamental role in cardiovascular pathophysiology to further support potential applications of exosomes as biomarkers and therapeutics for cardiovascular diseases. Show more

Involvement of cell-derived extracellular particles, coined as matrix vesicles (MVs), in biological bone formation was introduced by Bonucci and Anderson in mid-1960s. In 1983, Anderson et al. observed similar structures in atherosclerotic lesion calcification using electron microscopy. Recent studies employing new technologies and high- resolution microscopy have shown that although they exhibit characteristics similar to MVs, calcifying extracellular vesicles (EVs) in cardiovascular tissues are phenotypically distinct from their bone counterparts. EVs released from cells within cardiovascular tissues may contain either inhibitors of calcification in normal physiological conditions or promoters in pathological environments. Pathological conditions characterized by mineral imbalance (e.g., atherosclerosis, chronic kidney disease, diabetes) can cause smooth muscle cells, valvular interstitial cells, and macrophages to release calcifying EVs, which contain specific mineralization-promoting cargo. These EVs can arise from either direct budding of the cell plasma membrane or through the release of exosomes from multivesicular bodies. In contrast, MVs are germinated from specific sites on osteoblast, chondrocyte, or odontoblast membranes. Much like MVs, calcifying EVs in the fibrillar collagen extracellular matrix of cardiovascular tissues serve as calcification foci, but the mineral that forms appears different between the tissues. This review highlights recent studies on mechanisms of calcifying EV formation, release, and mineralization in cardiovascular calcification. Furthermore, we address the MV–EV relationship, and offer insight into therapeutic implications to consider for potential targets for each type of mineralization. Show more