Genesis and growth of extracellular-vesicle-derived microcalcification in atherosclerotic plaques

• Published in: Nature materials Vol. 15; no. 3; pp. 335 - 343
• Main Authors: Hutcheson, Joshua D., Goettsch, Claudia, Bertazzo, Sergio, Maldonado, Natalia, Ruiz, Jessica L., Goh, Wilson, Yabusaki, Katsumi, Faits, Tyler, Bouten, Carlijn, Franck, Gregory, Quillard, Thibaut, Libby, Peter, Aikawa, Masanori, Weinbaum, Sheldon, Aikawa, Elena
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.03.2016; Nature Publishing Group
• Subjects: 140/146; 639/166; 639/301/54; Animals; Apolipoproteins E - genetics; Apolipoproteins E - metabolism; Atherosclerosis; Atherosclerosis - metabolism; Biomaterials; Calcification; Calcium - metabolism; Carotid Arteries - pathology; Collagen; Collagen - metabolism; Collagens; Condensed Matter Physics; Coronary Disease - metabolism; Extracellular Matrix; Extracellular Vesicles - physiology; Failure; Formations; Genesis; Health risks; Humans; Hydrogels; Materials Science; Mice; Mice, Knockout; Minerals; Nanotechnology; Optical and Electronic Materials; Stress analysis; Three dimensional
• ISSN: 1476-1122; 1476-4660
• DOI: 10.1038/nmat4519

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 areas. We also show that calcification morphology and the plaque’s collagen content—two determinants of atherosclerotic plaque stability—are interlinked. The formation of atherosclerotic plaques involves the aggregation of calcifying extracellular vesicles and the formation of microcalcifications.