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Discoidin domain receptor-1 regulates calcific extracellular vesicle release in vascular smooth muscle cell fibrocalcific response via transforming growth factor-β signaling

Krohn, JB; Hutcheson, JD; Martínez-Martínez, E; Irvin, WS; Bouten, CVC; Bertazzo, S; Bendeck, MP; (2016) Discoidin domain receptor-1 regulates calcific extracellular vesicle release in vascular smooth muscle cell fibrocalcific response via transforming growth factor-β signaling. Arteriosclerosis, Thrombosis, and Vascular Biology , 36 (3) pp. 525-533. 10.1161/ATVBAHA.115.307009. Green open access

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Abstract

Objective - Collagen accumulation and calcification are major determinants of atherosclerotic plaque stability. Extracellular vesicle (EV)-derived microcalcifications in the collagen-poor fibrous cap may promote plaque rupture. In this study, we hypothesize that the collagen receptor discoidin domain receptor-1 (DDR-1) regulates collagen deposition and release of calcifying EVs by vascular smooth muscle cells (SMCs) through the transforming growth factor-β (TGF-β) pathway. Approach and Results - SMCs from the carotid arteries of DDR-1-/- mice and wild-type littermates (n=5-10 per group) were cultured in normal or calcifying media. At days 14 and 21, SMCs were harvested and EVs isolated for analysis. Compared with wild-type, DDR-1-/- SMCs exhibited a 4-fold increase in EV release (P<0.001) with concomitantly elevated alkaline phosphatase activity (P<0.0001) as a hallmark of EV calcifying potential. The DDR-1-/- phenotype was characterized by increased mineralization (Alizarin Red S and Osteosense, P<0.001 and P=0.002, respectively) and amorphous collagen deposition (P<0.001). We further identified a novel link between DDR-1 and the TGF-β pathway previously implicated in both fibrotic and calcific responses. An increase in TGF-β1 release by DDR-1-/- SMCs in calcifying media (P<0.001) stimulated p38 phosphorylation (P=0.02) and suppressed activation of Smad3. Inhibition of either TGF-β receptor-I or phospho-p38 reversed the fibrocalcific DDR-1-/- phenotype, corroborating a causal relationship between DDR-1 and TGF-β in EV-mediated vascular calcification. Conclusions - DDR-1 interacts with the TGF-β pathway to restrict calcifying EV-mediated mineralization and fibrosis by SMCs. We therefore establish a novel mechanism of cell-matrix homeostasis in atherosclerotic plaque formation.

Type: Article
Title: Discoidin domain receptor-1 regulates calcific extracellular vesicle release in vascular smooth muscle cell fibrocalcific response via transforming growth factor-β signaling
Open access status: An open access version is available from UCL Discovery
DOI: 10.1161/ATVBAHA.115.307009
Publisher version: http://doi.org/10.1161/ATVBAHA.115.307009
Language: English
Additional information: Copyright © 2016 American Heart Association, Inc. All rights reserved.
Keywords: Fibrosis, Extracellular Matrix, Transforming Growth Factors, Extracellular Vesicles, Smooth Muscle, Potential Implications, Alkaline-phosphatase, Tyrosine Kinases, Plaque Rupture, Collagen, Mineralization, Microcalcifications, Atherosclerosis, Differentiation, Expression
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > UCL BEAMS
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Engineering Science
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Engineering Science > Dept of Med Phys and Biomedical Eng
URI: https://discovery.ucl.ac.uk/id/eprint/1497313
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