Extracellular vesicles in cardiovascular calcification: expanding current paradigms

Abstract

Vascular calcification is a major contributor to the progression of cardiovascular disease, one of the leading causes of death in industrialized countries. New evidence on the mechanisms of mineralization identified calcification-competent extracellular vesicles (EVs) derived from smooth muscle cells, valvular interstitial cells and macrophages as the mediators of calcification in diseased heart valves and atherosclerotic plaques. However, the regulation of EV release and the mechanisms of interaction between EVs and the extracellular matrix leading to the formation of destabilizing microcalcifications remain unclear. This review focuses on current limits in our understanding of EVs in cardiovascular disease and opens up new perspectives on calcific EV biogenesis, release and functions within and beyond vascular calcification. We propose that, unlike bone-derived matrix vesicles, a large population of EVs implicated in cardiovascular calcification are of exosomal origin. Moreover, the milieu-dependent loading of EVs with microRNA and calcification inhibitors fetuin-A and matrix Gla protein suggests a novel role for EVs in intercellular communication, adding a new mechanism to the pathogenesis of vascular mineralization. Similarly, the cell type-dependent enrichment of annexins 2, 5 or 6 in calcifying EVs posits one of several emerging factors implicated in the regulation of EV release and calcifying potential. This review aims to emphasize the role of EVs as essential mediators of calcification, a major determinant of cardiovascular mortality. Based on recent findings, we pinpoint potential targets for novel therapies to slow down the progression and promote the stability of atherosclerotic plaques.

 Vessel wall-derived extracellular vesicles (EVs) are selectively loaded with calcification inhibitors fetuin-A, matrix Gla protein (MGP) and anti-osteogenic microRNA (miRNA) (green box) or pro-calcific annexins, alkaline phosphatase (ALP), calcium (Ca²⁺) and inorganic phosphate (P_i) (red box). Calcifying conditions (e.g. culture in osteogenic media, OM) increase absolute EV release and EV calcific potential by shifting the balance towards increased expression of pro-calcific factors and suppression of calcification inhibitors in EVs. EVs may originate from the exosomal pathway (1), as multivesicular bodies (MVB; observed but not confirmed in smooth muscle cells, SMCs) (2), or by budding off the cell membrane (not confirmed in SMCs) (3). While the exocytosis pathway is an established mechanism in SMC-mediated calcific EV release, the exact conditions and potential context specificity of these pathways of EV biogenesis are still unclear. Under physiological conditions, non-calcifying EVs transfer inhibitory factors and regulatory miRNA as a form of paracrine signalling, preventing osteogenic differentiation of adjacent cells. Under calcifying conditions, however, calcification-competent EVs are sequestered in the fibrillar matrix, nucleating calcium phosphate mineral. Dysregulated paracrine signalling resulting in an imbalance of calcification inhibitors and miRNA leads to increased osteogenic differentiation of vessel wall cells, expediting vascular calcification.

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