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

Abstract

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.

Cell-matrix mechanics and pattern formation in inflammatory cardiovascular calcification

“…14 21 22 In bone, matrix vesicles secreted by osteoblasts serve as initiation sites for mineral crystal formation. In human vascular and valvular calcification, matrix vesicles appear to have the same role, 23 and these may be produced by both macrophages 24 and vascular smooth muscle cells. 25 Both vascular-derived and osteoblast-derived matrix vesicles contain calcium-binding and mineralisation-regulating proteins.…”

A materials science vision of extracellular matrix mineralization

“…It is conceivable that the inflammatory component is more characteristic of local cardiovascular calcification primarily associated with cell transdifferentiation 87 , whereas systemic vascular calcification is rather induced, independently of inflammation by metabolic imbalance and alteration of the ionic equilibrium 83 . Although atherosclerosis-associated vascular calcification merits a separate review, it is intriguing from the biomechanical perspective that a higher heterogeneity of a calcifying plaque, and the presence of numerous interfaces between its organic and inorganic constituents, lead to plaque instability and higher risk of disintegration followed by thrombosis 88 . In contrast, macrocalcification of the plaque sustains plaque integrity and bears a lesser risk of thrombosis 88 .…”

“…Although atherosclerosis-associated vascular calcification merits a separate review, it is intriguing from the biomechanical perspective that a higher heterogeneity of a calcifying plaque, and the presence of numerous interfaces between its organic and inorganic constituents, lead to plaque instability and higher risk of disintegration followed by thrombosis 88 . In contrast, macrocalcification of the plaque sustains plaque integrity and bears a lesser risk of thrombosis 88 . To compare to physiological mineralization, in bone the presence of abundant interfaces with abruptly changing moduli is essential for adequate toughness 50 .…”

Matrix metalloproteinase-3 gene polymorphism (rs3025058) affects markers atherosclerosis in type 2 diabetes mellitus

“…The pathogenesis of atherosclerosis is very complex, and several genes and their products have so far been implicated in the pathogenesis of atherosclerosis [5][6][7][8]. A very interesting candidate gene system is the matrix metalloproteinase (MMP) family.…”

“…A very interesting candidate gene system is the matrix metalloproteinase (MMP) family. The MMPs are proteolytic enzymes that degrade the extracellular matrix, leading to connective tissue remodelling during normal and pathological vascular remodelling [5][6][7][8].…”