Abstract
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.
Highlights
Bonucci reported the appearance of “roundish bodies” in initiation of the calcification process in guinea pig and rat tibial–femoral epiphyseal plates in 1967 [1]
The current review focuses on extracellular vesicles (EVs) that play a direct role in depositing mineral in cardiovascular tissues
Advancements in EV characterization tools may allow careful comparative studies to understand the similarities and differences between matrix vesicles (MVs) and calcifying EVs liberated from the three reported cellular contributors to calcification in cardiovascular tissues: vascular smooth muscle cells (SMCs), macrophages, and valvular interstitial cells (VICs)
Summary
Bonucci reported the appearance of “roundish bodies” in initiation of the calcification process in guinea pig and rat tibial–femoral epiphyseal plates in 1967 [1]. MVs interact with ECM proteins via their integrin receptors and surface motifs, such as CD9, CD63, and Hsp70 [5] (Figure 1) In addition to their remodeling potential and ECM binding, MVs in growth plate ECM can affect the proliferation and fate of resident cells, due to the activation of parathyroid hormones and gene-related peptide through their loaded proteins [5]. This paracrine signaling property is similar to other subtypes of extracellular vesicles (EVs) ubiquitous to many cells and tissues. Current evidence, discussed suggests that these EVs share commonalities with both MVs and other EV populations, such as exosomes
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