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The CCN Genes as the “Master” Regulators of Angiogenesis, Vasculogenesis, Fibrogenesis and Cell Differentiation/Fate Specification in Mechanical Force-Driven Developmental Processes and Pathological Events

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CCN Proteins in Health and Disease

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Abstract

Mechanical forces, whether internally generated or externally imposed, are an important determinant of tissue structure and function in physiological and pathological states and for engineering functional tissue constructs in vitro. Similarly, embryonic and fetal development of a variety of tissues is, at least in part, orchestrated by mechanical cues although such influence is seldom acknowledged because it is difficult to elaborate experimentally in vivo. How cells respond/adapt to variations in mechanical forces is critical in homeostasis and many diseases. Mechanical stimuli are sensed by mechanosensors at both the cell-extracellular matrix (ECM) interface and cell-cytoskeletal interface leading to the activation of signaling cascades that culminate into actin cytoskeletal remodeling and epigenetic modifications of chromatin. The ultimate targets are nuclear transcriptional elements that regulate the expression of numerous fetal genes including a subset of inducible ECM-associated proteins referred to as Cysteine-rich protein 61 (Cyr61 or CCN1) and connective tissue growth factor (CTGF or CCN2). CCN1 and CCN2 are structurally-related and functionally multifaceted multimodular proteins that appear in the extracellular environment particularly during development, pathological states and tissue repair and regeneration. CCN1 and CCN2 promote integrin-mediated adhesion, migration and/or chemotaxis and regulate the mitogenic and proapoptotic activities of cytokines and growth factors vis-à-vis the “mechanocytes” e.g., fibroblasts and endothelial, muscle and epithelial cells. Their apparently disparate activities, some mutually exclusive, are cell type-, cell signal- and cell context-dependent and re-enact developmental events such as angiogenesis, vasculogenesis, differentiation and fibrogenesis. This chapter discusses what has been learned lately about the role of mechanical forces in development and diseases of distensible organ systems and the role of CCN1 and CCN2 in the adaptive capabilities and maladaptive responses of tissues to mechanical overload.

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Abbreviations

ECM:

extracellular matrix

MAP:

mitogen-activated protein

FA:

focal adhesion

Cyr61:

Cysteine-rich protein 61

CTGF:

connective tissue growth factor

VEGF:

vascular endothelial growth factor

GSK-3b:

Glycogen synthase kinase 3 beta

LRP:

low density lipoprotein receptor-related protein

MHC:

myosin heavy chain

CREB:

cyclic AMP responsive element binding

FZD:

Frizzled homolog

MMP:

matrix metalloproteinase

TIMP:

tissue inhibitor of metalloproteinases

EPC:

endothelial progenitor cell

SRF:

serum response factor

MRTF:

myocardin-related transcription factor

PKC:

protein kinase C

PI 3-K:

phosphatidyl inositol 3-kinase.

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Acknowledgments

This work was supported by grants from the NIH/National Institute of Diabetes Digestive and Kidney Diseases, R01DK060572, 1R21EY019387-01A1, R56DK60572 (to B. C.).

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Authors and Affiliations

  1. Department of Cell Biology, State University of New York, Downstate Medical Center, 450 Clarkson Avenue, Box 5, Brooklyn, NY, 11203, USA

    Brahim Chaqour

  2. Department of Cell Biology, State University of New York (SUNY) Downstate Medical Center, Brooklyn, NY, 11203, USA

    Mary Hanna

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  1. Mary Hanna
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  2. Brahim Chaqour
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Correspondence to Brahim Chaqour .

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  1. Med Sci-I 6447, Ann Arbor, 48109, USA

    Annick Perbal

  2. Shikata-Cho 2-5-1, Okayama, 700-8525, Japan

    Masaharu Takigawa

  3. Palais du Grand Large, International CCN Society, Saint-Malo, France

    Bernard Perbal

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Hanna, M., Chaqour, B. (2010). The CCN Genes as the “Master” Regulators of Angiogenesis, Vasculogenesis, Fibrogenesis and Cell Differentiation/Fate Specification in Mechanical Force-Driven Developmental Processes and Pathological Events. In: Perbal, A., Takigawa, M., Perbal, B. (eds) CCN Proteins in Health and Disease. Springer, Dordrecht. https://doi.org/10.1007/978-90-481-3779-4_5

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