Calcific diseases of the cardiovascular system, such as atherosclerotic calcification and calcific aortic valve disease, are widespread and clinically significant, causing substantial morbidity and mortality. Vascular cells, like bone cells, interact with their matrix substrate through molecular signals, and through biomechanical signals, such as traction forces transmitted from cytoskeleton to matrix. The interaction of contractile vascular cells with their matrix may be one of the most important factors controlling pathological mineralisation of the artery wall and cardiac valves. In many respects, the matricrine and matrix mechanical changes in calcific vasculopathy and valvulopathy resemble those occurring in embryonic bone development and normal bone mineralisation. The matrix proteins provide a microenvironment for propagation of crystal growth and provide mechanical cues to the cells that direct differentiation. Small contractions of the cytoskeleton may tug on integrin links to sites on matrix proteins, and thereby sense the stiffness, possibly through deformation of binding proteins causing release of differentiation factors such as products of the members of the transforming growth factor-β superfamily. Inflammation and matrix characteristics are intertwined: inflammation alters the matrix such as through matrix metalloproteinases, while matrix mechanical properties affect cellular sensitivity to inflammatory cytokines. The adhesive properties of the matrix also regulate self-organisation of vascular cells into patterns through reaction-diffusion phenomena and left-right chirality. In this review, we summarise the roles of extracellular matrix proteins and biomechanics in the development of inflammatory cardiovascular calcification.
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Contributors JJH, JL, YT and LLD contributed to layout and editing of the overall content of the work described in the article. JJH, JL, YT and LLD each contributed to parts of the writing, and JJH contributed to the artwork.
Funding This work was supported by funding from the Heart Lung and Blood Institute of the National Institutes of Health, (HL114709 and HL121019). JJH was supported by a T32 training grant from the National Institutes of Health (HL007895) and an award from the UCLA Specialty Training and Advanced Research (STAR) Program. JL was supported by the UCLA Children's Discovery and Innovation Institute Harry Winston Fellowship Award.
Competing interests None declared.
Provenance and peer review Commissioned; internally peer reviewed.
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