Evidence map›Paper›PMID 26800565›Full record

ArticleArteriosclerosis, thrombosis, and vascular biology2016

Discoidin Domain Receptor-1 Regulates Calcific Extracellular Vesicle Release in Vascular Smooth Muscle Cell Fibrocalcific Response via Transforming Growth Factor-β Signaling.

Jona B Krohn, Joshua D Hutcheson, Eduardo Martínez-Martínez, Whitney S Irvin, Carlijn V C Bouten, Sergio Bertazzo, Michelle P Bendeck, Elena Aikawa

Open access · bronzeAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Arteriosclerosis, thrombosis, and vascular biology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 45 papers.

0numbers the graph read from it
0cells of the map it votes in
45citing papers in PubMed
7.1field-weighted citation impact, top 2% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

45 citing papers in PubMed, 72 citations in OpenAlex.

  1. Trial
  2. Review
  3. Plasma-Derived Extracellular Vesicle Proteomics.Journal of proteome research · 2025
    Review
  4. Article
  5. Article
  6. Article
  7. Review
  8. Review
  9. Review
  10. Review
  11. Article
  12. Article
  13. Review
  14. Review
  15. Review
  16. Matrix Vesicles as a Therapeutic Target for Vascular Calcification.Frontiers in cell and developmental biology · 2022
    Review
  17. Article
  18. Regulatory role of mammalian target of rapamycin signaling in exosome secretion and osteogenic changes in smooth muscle cells lacking acid ceramidase gene.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2021
    Article
  19. Article
  20. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

8 authors at 2 institutions in 2 countries.

Jona B KrohnFrom the Department of Medicine, Cardiovascular Division, Center for Excellence in Vascular Biology (J.B.K., E.M.-M., W.S.I., E.A.) and Center for Interdisciplinary Cardiovascular Sciences (J.D.H., E.A.), Harvard Medical School, Boston, MA; Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands (C.V.C.B.); Department of Medical Physics and Biomedical Engineering, University College London, London, United Kingdom (S.B.); and Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada (M.P.B.).
Joshua D HutchesonFrom the Department of Medicine, Cardiovascular Division, Center for Excellence in Vascular Biology (J.B.K., E.M.-M., W.S.I., E.A.) and Center for Interdisciplinary Cardiovascular Sciences (J.D.H., E.A.), Harvard Medical School, Boston, MA; Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands (C.V.C.B.); Department of Medical Physics and Biomedical Engineering, University College London, London, United Kingdom (S.B.); and Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada (M.P.B.).
Eduardo Martínez-MartínezFrom the Department of Medicine, Cardiovascular Division, Center for Excellence in Vascular Biology (J.B.K., E.M.-M., W.S.I., E.A.) and Center for Interdisciplinary Cardiovascular Sciences (J.D.H., E.A.), Harvard Medical School, Boston, MA; Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands (C.V.C.B.); Department of Medical Physics and Biomedical Engineering, University College London, London, United Kingdom (S.B.); and Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada (M.P.B.).
Whitney S IrvinFrom the Department of Medicine, Cardiovascular Division, Center for Excellence in Vascular Biology (J.B.K., E.M.-M., W.S.I., E.A.) and Center for Interdisciplinary Cardiovascular Sciences (J.D.H., E.A.), Harvard Medical School, Boston, MA; Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands (C.V.C.B.); Department of Medical Physics and Biomedical Engineering, University College London, London, United Kingdom (S.B.); and Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada (M.P.B.).
Carlijn V C BoutenFrom the Department of Medicine, Cardiovascular Division, Center for Excellence in Vascular Biology (J.B.K., E.M.-M., W.S.I., E.A.) and Center for Interdisciplinary Cardiovascular Sciences (J.D.H., E.A.), Harvard Medical School, Boston, MA; Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands (C.V.C.B.); Department of Medical Physics and Biomedical Engineering, University College London, London, United Kingdom (S.B.); and Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada (M.P.B.).
Sergio BertazzoFrom the Department of Medicine, Cardiovascular Division, Center for Excellence in Vascular Biology (J.B.K., E.M.-M., W.S.I., E.A.) and Center for Interdisciplinary Cardiovascular Sciences (J.D.H., E.A.), Harvard Medical School, Boston, MA; Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands (C.V.C.B.); Department of Medical Physics and Biomedical Engineering, University College London, London, United Kingdom (S.B.); and Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada (M.P.B.).
Michelle P BendeckFrom the Department of Medicine, Cardiovascular Division, Center for Excellence in Vascular Biology (J.B.K., E.M.-M., W.S.I., E.A.) and Center for Interdisciplinary Cardiovascular Sciences (J.D.H., E.A.), Harvard Medical School, Boston, MA; Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands (C.V.C.B.); Department of Medical Physics and Biomedical Engineering, University College London, London, United Kingdom (S.B.); and Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada (M.P.B.).
Elena AikawaFrom the Department of Medicine, Cardiovascular Division, Center for Excellence in Vascular Biology (J.B.K., E.M.-M., W.S.I., E.A.) and Center for Interdisciplinary Cardiovascular Sciences (J.D.H., E.A.), Harvard Medical School, Boston, MA; Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands (C.V.C.B.); Department of Medical Physics and Biomedical Engineering, University College London, London, United Kingdom (S.B.); and Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada (M.P.B.). eaikawa@partners.org jdhutcheson@partners.org.
University College London · GBEindhoven University of Technology · NL

Funding

Improving Mitral Compensation in Ischemic RegurgitationR01HL109506 · NHLBI · MASSACHUSETTS GENERAL HOSPITAL · PI AIKAWA, ELENA, BISCHOFF, JOYCE E. · 2012 to 2015
$3.3M
Aortic valve microcalcificationR01HL114805 · NHLBI · BRIGHAM AND WOMEN'S HOSPITAL · PI AIKAWA, ELENA · 2012 to 2016
$2.1M
Canadian Institutes of Health Research MOP133592NHLBI NIH HHS R01 HL109506NHLBI NIH HHS R01HL109506NHLBI NIH HHS R01 HL114805NHLBI NIH HHS R01HL114805
6 · The paper itself

Abstract

objectiveCollagen 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

resultsSMCs 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.

conclusionsDDR-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.

Indexed as

AnimalsApolipoproteins EAtherosclerosisCells, CulturedCollagenDiscoidin Domain Receptor 1Disease Models, AnimalExtracellular VesiclesFemaleFibrosisGenetic Predisposition to DiseaseMaleMice, 129 StrainMice, Inbred C57BLMice, KnockoutMuscle, Smooth, VascularApolipoproteins ECollagenDdr1 protein, mouseDiscoidin Domain Receptor 1p38 Mitogen-Activated Protein KinasesProtein Serine-Threonine KinasesReceptor Protein-Tyrosine KinasesReceptors, Transforming Growth Factor betaReceptor, Transforming Growth Factor-beta Type ISmad3 ProteinSMAD3 protein, humanTgfb1 protein, mouseTransforming Growth Factor beta1extracellular matrixextracellular vesiclesfibrosissmooth muscletransforming growth factors

Identifiers

PMID26800565
PMCPMC4767541
OpenAlexW2284045575

What OpenQuestion holds

Textmetadata
LicenceTDM
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.