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Cardiac Fibrosis and Heart Failure: Cause or Effect? pp 23–53Cite as

Mechanical and Matrix Regulation of Valvular Fibrosis

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Part of the book series: Advances in Biochemistry in Health and Disease ((ABHD,volume 13))

Abstract

The aortic valve lies in, arguably, one of the more complex local mechanobiological environments in the body. The inherent intricacy of this microenvironment results in multiple homeostatic mechanisms, but also a wide variety of putative disease pathways by which valve function can be compromised. Aortic valve disease (AVD) is a cell-mediated pathology whose initial stages are characterized by unchecked matrix dysregulation, leaflet thickening, and widespread fibrosis. The valve itself is composed of multiple cell populations, including endothelial cells that are sensitive to blood flow-induced shear stresses and multipotent mesenchymal progenitors which are influenced by both the mechanical properties and composition of the surrounding extracellular matrix. Dynamic mechanical loading and shear stresses over the cardiac cycle, an irregular three-dimensional shape, and a non-uniform matrix composition further influence these cellular responses. There is also abundant biochemical signaling in the aortic root, with molecular factors either produced by valve cells or transported to the root via blood flow. When these mechanical/biochemical processes become deregulated as a result of insults to their constituent components, resident valvular cells are driven to undergo myofibroblastic differentiation, a program of valvular fibrosis sets in, and valve function is compromised. Valve dysfunction affects the cardiac environment as well, as impaired opening and reductions in orifice area alter myocardial mechanics and often result in hypertrophy and/or fibrosis of the left ventricle. In this chapter, we use the aortic valve as a model tissue to discuss causative mechanisms of cardiovascular fibrosis, including the contributions of mechanotransduction, matrix dysregulation, and biochemical signaling.

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Abbreviations

5-HT:

5-hydroxytryptamine (serotonin)

5-HT2A :

5-hydroxytryptamine receptor 2A

α-SMA:

α-smooth muscle actin

ACEi:

Angiotensin converting enzyme inhibitor

ARB:

Angiotensin receptor blocker

AVD:

Aortic valve disease

BMP:

Bone morphogenic protein

CAVD:

Calcific aortic valve disease

CNP:

C-type natriuretic peptide

EC:

Endothelial cell (vascular)

ECM:

Extracellular matrix

EndMT:

Endothelial-to-mesenchymal transition

FA:

Focal adhesion

FAK:

Focal adhesion kinase

FGF-2:

Basic fibroblast growth factor-2

GAP:

GTPase-activating protein

GEF:

Guanine nucleotide exchange factor

LAP:

Latency associated peptide

LC:

Left coronary (cusp)

LLC:

Large latent complex

LTBP-1:

Latent TGF-β1 binding protein-1

mDia:

Mammalian diaphanous-related formin

MyHC:

Heavy chain smooth muscle myosin

MLC:

Myosin light chain

MMP:

Matrix metalloproteinase

MRTF-A:

Myocardin-related transcription factor-A

NC:

Non-coronary (cusp)

NPR-B:

Natriuretic peptide receptor-B

PKG:

Protein kinase-G

RC:

Right coronary (cusp)

ROCK:

Rho-associated protein kinase

SRF:

Serum response factor

TGF-β1:

Transforming growth factor-β1

TGFβRI/II:

TGFβ receptor I/II

TIMPs:

Tissue inhibitors of metalloproteinases

TNFα :

Tumor necrosis factor-α

VEC:

Valvular endothelial cell

VIC:

Valvular interstitial cell

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Acknowledgements

This work was supported by the Canadian Institutes of Health Research, the National Science and Engineering Research Council of Canada, and the Heart and Stroke Foundation of Ontario. We gratefully acknowledge Dr. Krista Sider for providing images of porcine aortic valves .

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Authors and Affiliations

  1. Institute of Biomaterials and Biomedical Engineering, University of Toronto, 5 King’s College Road, Rm. 221, M5S 3G8, Toronto, ON, Canada

    Mark C. Blaser & Dr. Craig A. Simmons

  2. Cardiovascular Sciences Collaborative Program, University of Toronto, Toronto, Canada

    Mark C. Blaser & Dr. Craig A. Simmons

  3. Department of Mechanical and Industrial Engineering, University of Toronto, Toronto, Canada

    Dr. Craig A. Simmons

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  1. Mark C. Blaser
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Correspondence to Craig A. Simmons .

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  1. Institute of Cardiovascular Sciences St. Boniface Hospital Research Centre Department of Physiology and Pathophysiology, University of Manitoba, Winnipeg, Canada

    Ian M.C. Dixon

  2. Institute of Cardiovascular Sciences St. Boniface Hospital Research Centre Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Canada

    Jeffrey T. Wigle

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Blaser, M., Simmons, C. (2015). Mechanical and Matrix Regulation of Valvular Fibrosis. In: Dixon, I., Wigle, J. (eds) Cardiac Fibrosis and Heart Failure: Cause or Effect?. Advances in Biochemistry in Health and Disease, vol 13. Springer, Cham. https://doi.org/10.1007/978-3-319-17437-2_3

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