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Cell-matrix mechanics and pattern formation in inflammatory cardiovascular calcification
  1. Jeffrey J Hsu1,
  2. Jina Lim2,
  3. Yin Tintut1,3,4,
  4. Linda L Demer1,3,5
  1. 1Department of Medicine, Division of Cardiology, University of California, Los Angeles (UCLA), Los Angeles, California, USA
  2. 2Department of Pediatrics, University of California, Los Angeles (UCLA), Los Angeles, California, USA
  3. 3Department of Physiology, University of California, Los Angeles (UCLA), Los Angeles, California, USA
  4. 4Department of Orthopaedic Surgery, University of California, Los Angeles (UCLA), Los Angeles, California, USA
  5. 5Department of Bioengineering, University of California, Los Angeles (UCLA), Los Angeles, California, USA
  1. Correspondence to Dr Linda Demer, The David Geffen School of Medicine, Center for the Health Sciences A2-237, University of California, 10833 Le Conte Ave, Los Angeles, CA 90095-1679, USA; ldemer{at}mednet.ucla.edu

Abstract

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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