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The Role of DDRs in Atherosclerosis

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Discoidin Domain Receptors in Health and Disease

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Abstract

Discoidin domain receptors are unique collagen-binding receptors known to play important roles in mediating cell proliferation, migration, and the production of matrix metalloproteinases by cells during development and in several fibroinflammatory diseases. Collagens are abundant in human vascular and atherosclerotic lesions and play critical roles as bioactive molecules mediating cellular responses to injury. Collagens also affect the long-term complications of atherosclerosis including vascular calcification and plaque rupture. This review chapter summarizes the literature reporting an important role for DDR1 in atherosclerosis. DDR1 and DDR2 are both expressed in rodent and primate models of the disease. Our studies using mouse models of atherosclerosis have shown that DDR1 mediates plaque expansion and inflammation, but suppresses matrix accumulation, leading to the development of unstable plaques which are prone to rupture. DDR1 is required for macrophage infiltration of the atherosclerotic plaque, permitting attachment to and invasion through type IV collagen in the subendothelial cell basement membrane. DDR1 is also involved in mediating the production of MMPs and inflammatory cytokines in both macrophages and smooth muscle cells. In addition, DDR1 plays an important role in vascular atherosclerotic calcification, by mediating smooth muscle cell transdifferentiation, and by compounding inflammatory cytokine production by macrophages. Evidence suggests that inhibition of DDR1 may be a good therapeutic target for atherosclerosis, since DDR1 inhibition would lead to smaller, less inflammatory more stable, and less calcified atherosclerotic plaques.

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Authors and Affiliations

  1. Department of Laboratory Medicine and Pathobiology, University of Toronto, Ted Rogers Centre for Heart Research, 661 University Ave., 14th Floor, Toronto, ON, Canada, M5G1M1

    Michelle P. Bendeck

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  1. Michelle P. Bendeck
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Correspondence to Michelle P. Bendeck .

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Editors and Affiliations

  1. Department of Pathology, Wayne State University School of Medicine and Karmanos Cancer Institute, Detroit, Michigan, USA

    Rafael Fridman

  2. Division of Cancer Biology, The Institute of Cancer Research, London, United Kingdom

    Paul H. Huang

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Bendeck, M.P. (2016). The Role of DDRs in Atherosclerosis. In: Fridman, R., Huang, P. (eds) Discoidin Domain Receptors in Health and Disease. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-6383-6_17

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