Macrophages promote endothelial-to-mesenchymal transition via MT1-MMP/TGFβ1 after myocardial infarction

  1. Laura Alonso-Herranz  Is a corresponding author
  2. Álvaro Sahún-Español
  3. Ana Paredes
  4. Pilar Gonzalo
  5. Polyxeni Gkontra
  6. Vanessa Núñez
  7. Cristina Clemente
  8. Marta Cedenilla
  9. María Villalba-Orero
  10. Javier Inserte
  11. David García-Dorado
  12. Alicia G Arroyo
  13. Mercedes Ricote  Is a corresponding author
  1. Centro Nacional de Investigaciones Cardiovasculares, Spain
  2. Vall d'Hebron University Hospital and Research Institute, Spain
  3. Centro de Investigaciones Biológicas (CIB-CSIC), Spain

Abstract

Macrophages (Mφs) produce factors that participate in cardiac repair and remodeling after myocardial infarction (MI); however, how these factors crosstalk with other cell types mediating repair is not fully understood. Here, we demonstrated that cardiac Mφs increased expression of Mmp14 (MT1-MMP) 7 days post-MI. We selectively inactivated the Mmp14 gene in Mφs using a genetic strategy (Mmp14f/f:Lyz2-Cre). This conditional KO (MAC-Mmp14 KO) resulted in attenuated post-MI cardiac dysfunction, reduced fibrosis, and preserved cardiac capillary network. Mechanistically, we showed that MT1-MMP activates latent TGFβ1 in Mφs, leading to paracrine SMAD2-mediated signaling in endothelial cells (ECs) and endothelial-to-mesenchymal transition (EndMT). Post-MI MAC-Mmp14 KO hearts contained fewer cells undergoing EndMT than their wild-type counterparts, and Mmp14-deficient Mφs showed a reduced ability to induce EndMT in co-cultures with ECs. Our results indicate the contribution of EndMT to cardiac fibrosis and adverse remodeling post-MI and identify Mφ MT1-MMP as a key regulator of this process.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for all the figures.

Article and author information

Author details

  1. Laura Alonso-Herranz

    Myocardial Pathophysiology Area, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain
    For correspondence
    laura.alonso348@gmail.com
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0880-4735
  2. Álvaro Sahún-Español

    Vascular Pathophysiology Area, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain
    Competing interests
    The authors declare that no competing interests exist.
  3. Ana Paredes

    Pathophysiology of the Myocardium, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain
    Competing interests
    The authors declare that no competing interests exist.
  4. Pilar Gonzalo

    Vascular Pathophysiology Area, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain
    Competing interests
    The authors declare that no competing interests exist.
  5. Polyxeni Gkontra

    Vascular Pathophysiology Area, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain
    Competing interests
    The authors declare that no competing interests exist.
  6. Vanessa Núñez

    Myocardial Pathophysiology Area, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain
    Competing interests
    The authors declare that no competing interests exist.
  7. Cristina Clemente

    Vascular Pathophysiology Area, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain
    Competing interests
    The authors declare that no competing interests exist.
  8. Marta Cedenilla

    Myocardial Pathophysiology Area, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain
    Competing interests
    The authors declare that no competing interests exist.
  9. María Villalba-Orero

    Myocardial Pathophysiology Area, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain
    Competing interests
    The authors declare that no competing interests exist.
  10. Javier Inserte

    Vascular Biology and Metabolism, Vall d'Hebron University Hospital and Research Institute, Barcelona, Spain
    Competing interests
    The authors declare that no competing interests exist.
  11. David García-Dorado

    Vascular Biology and Metabolism, Vall d'Hebron University Hospital and Research Institute, Barcelona, Spain
    Competing interests
    The authors declare that no competing interests exist.
  12. Alicia G Arroyo

    Matrix Metalloproteinases in Angiogenesis and Inflammationnflamación, Centro de Investigaciones Biológicas (CIB-CSIC), Madrid, Spain
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1536-3846
  13. Mercedes Ricote

    Myocardial Pathophysiology Area, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain
    For correspondence
    mricote@cnic.es
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8090-8902

Funding

Spanish Ministry of Science, Innovation and Universities (SAF2017-90604-REDT-NurCaMein)

  • Mercedes Ricote

Spanish Ministry of Science, Innovation and Universities (RTI2018-095928-BI00)

  • Mercedes Ricote

Spanish Ministry of Science, Innovation and Universities (SAF2017-83229-R)

  • Alicia G Arroyo

Comunidad de Madrid (MOIR-B2017/BMD-3684)

  • Alicia G Arroyo

La Marato TV3 Foundation

  • David García-Dorado
  • Alicia G Arroyo
  • Mercedes Ricote

Fundacion La Caixa

  • Laura Alonso-Herranz
  • Álvaro Sahún-Español

La Residencia de Estudiantes

  • Álvaro Sahún-Español

FORD-Spain and Apadrina La Ciencia

  • Álvaro Sahún-Español

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Noriaki Emoto, Kobe Pharmaceutical University, Japan

Ethics

Animal experimentation: All animal procedures were conducted in accordance with EU Directive 86/609/EEC and approved by the Animal Subjects Committee of the Instituto de Salud Carlos III (Madrid, Spain) and Madrid Community Organs in the PROEX 188/26. All surgery was performed under anesthesia with sevoflurane (5% for induction, 2%-3% for maintenance) and buprenorphine (0.01 mg/kg, Buprex, Merck & Co. Inc) was given for pain relief.

Version history

  1. Received: April 15, 2020
  2. Accepted: October 15, 2020
  3. Accepted Manuscript published: October 16, 2020 (version 1)
  4. Accepted Manuscript updated: October 21, 2020 (version 2)
  5. Version of Record published: November 3, 2020 (version 3)

Copyright

© 2020, Alonso-Herranz et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Laura Alonso-Herranz
  2. Álvaro Sahún-Español
  3. Ana Paredes
  4. Pilar Gonzalo
  5. Polyxeni Gkontra
  6. Vanessa Núñez
  7. Cristina Clemente
  8. Marta Cedenilla
  9. María Villalba-Orero
  10. Javier Inserte
  11. David García-Dorado
  12. Alicia G Arroyo
  13. Mercedes Ricote
(2020)
Macrophages promote endothelial-to-mesenchymal transition via MT1-MMP/TGFβ1 after myocardial infarction
eLife 9:e57920.
https://doi.org/10.7554/eLife.57920

Share this article

https://doi.org/10.7554/eLife.57920

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