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

J.B. Krohn, J.D. Hutcheson, E. Martínez-Martínez, W.S. Irvin, C.V.C. Bouten, S. Bertazzo, M.P. Bendeck, E. Aikawa

Research output: Contribution to journalArticleAcademicpeer-review

39 Citations (Scopus)
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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-/- phenotype was characterized by increased mineralization (Alizarin Red S and Osteosense, P-/- SMCs in calcifying media (P-/- 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.

Original languageEnglish
Pages (from-to)525-533
Number of pages9
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume36
Issue number3
DOIs
Publication statusPublished - 1 Mar 2016

Keywords

  • extracellular matrix
  • extracellular vesicles
  • fibrosis
  • smooth muscle
  • transforming growth factors

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