1. Human Biology and Medicine
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Mechanistic insights into a TIMP3-sensitive pathway constitutively engaged in the regulation of cerebral hemodynamics

  1. Carmen Capone
  2. Fabrice Dabertrand
  3. Celine Baron-Menguy
  4. Athena Chalaris
  5. Lamia Ghezali
  6. Valérie Domenga-Denier
  7. Stefanie Schmidt
  8. Clément Huneau
  9. Stefan Rose-John
  10. Mark T Nelson
  11. Anne Joutel  Is a corresponding author
  1. INSERM, France
  2. University of Vermont, United States
  3. Institute of Biochemistry, Medical Faculty, Christian Albrechts University, Germany
  4. University of Vermont, University of Manchester, United States
Research Article
  • Cited 25
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Cite this article as: eLife 2016;5:e17536 doi: 10.7554/eLife.17536

Abstract

Cerebral small vessel disease (SVD) is a leading cause of stroke and dementia. CADASIL, an inherited SVD, alters cerebral artery function, compromising blood flow to the working brain. TIMP3 (tissue inhibitor of metalloproteinase 3) accumulation in the vascular extracellular matrix in CADASIL is a key contributor to cerebrovascular dysfunction. However, the linkage between elevated TIMP3 and compromised cerebral blood flow (CBF) remains unknown. Here, we show that TIMP3 acts through inhibition of the metalloprotease ADAM17 and HB-EGF to regulate cerebral arterial tone and blood flow responses. In a clinically relevant CADASIL mouse model, we show that exogenous ADAM17 or HB-EGF restores cerebral arterial tone and blood flow responses, and identify upregulated voltage-dependent potassium channel (KV) number in cerebral arterial myocytes as a heretofore-unrecognized downstream effector of TIMP3-induced deficits. These results support the concept that the balance of TIMP3 and ADAM17 activity modulates CBF through regulation of myocyte KV channel number.

Article and author information

Author details

  1. Carmen Capone

    Genetics and Pathophysiology of Cerebrovascular Diseases, INSERM, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  2. Fabrice Dabertrand

    Department of Pharmacology, University of Vermont, Burlington, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Celine Baron-Menguy

    Genetics and Pathophysiology of Cerebrovascular Diseases, INSERM, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  4. Athena Chalaris

    Molecular Biology of Cytokines, Institute of Biochemistry, Medical Faculty, Christian Albrechts University, Kiel, Germany
    Competing interests
    The authors declare that no competing interests exist.
  5. Lamia Ghezali

    Genetics and Pathophysiology of Cerebrovascular Diseases, INSERM, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  6. Valérie Domenga-Denier

    Genetics and Pathophysiology of Cerebrovascular Diseases, INSERM, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  7. Stefanie Schmidt

    Molecular Biology of Cytokines, Institute of Biochemistry, Medical Faculty, Christian Albrechts University, Kiel, Germany
    Competing interests
    The authors declare that no competing interests exist.
  8. Clément Huneau

    Genetics and Pathophysiology of Cerebrovascular Diseases, INSERM, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  9. Stefan Rose-John

    Molecular Biology of Cytokines, Institute of Biochemistry, Medical Faculty, Christian Albrechts University, Kiel, Germany
    Competing interests
    The authors declare that no competing interests exist.
  10. Mark T Nelson

    Department of Pharmacology, University of Vermont, University of Manchester, Burlington, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Anne Joutel

    Genetics and Pathophysiology of Cerebrovascular Diseases, INSERM, Paris, France
    For correspondence
    anne.joutel@inserm.fr
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3963-3860

Funding

Agence Nationale de la Recherche (ANR Genopath 2009-RAE09011HSA and ANR Blanc 2010-RPV11011HHA)

  • Anne Joutel

Fondation Leducq (Transatlantic Network of Excellence on the Pathogenesis of Small Vessel Disease of the Brain)

  • Mark T Nelson
  • Anne Joutel

European Union (Horizon 2020 research and innovation programme SVDs@target, grant agreement No 666881)

  • Mark T Nelson
  • Anne Joutel

National Institute of Health (R37DK053832, PO1HL095488, RO1HL44455, R01HL121706, R01HL131181)

  • Mark T Nelson

Totman Medical Research Trust

  • Mark T Nelson

United Leukodystrophy Foundation (CADASIL Research Grant)

  • Fabrice Dabertrand

Deutsche Forschungsgemeinschaft (DFG, SFB877 project A1 and the Cluster of Excellence Inflammation at Interfaces)

  • Athena Chalaris
  • Stefan Rose-John

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

Ethics

Animal experimentation: All experiments were conducted in full accordance with the French guidelines for the use of animals in research and were approved by the "Lariboisière-Villemin" Institutional Animal Care and Use Committee (C2EA 09), with every effort made to minimize the number of animals used.

Reviewing Editor

  1. David E Clapham, Howard Hughes Medical Institute, Boston Children's Hospital, United States

Publication history

  1. Received: May 5, 2016
  2. Accepted: July 30, 2016
  3. Accepted Manuscript published: August 1, 2016 (version 1)
  4. Version of Record published: August 22, 2016 (version 2)

Copyright

© 2016, Capone 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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