Myogenic vasoconstriction requires G12/G13 and LARG to maintain local and systemic vascular resistance

  1. Ramesh Chennupati
  2. Angela Wirth
  3. Julie Favre
  4. Rui Li
  5. Rémy Bonnavion
  6. Young-June Jin
  7. Astrid Wietelmann
  8. Frank Schweda
  9. Nina Wettschureck
  10. Daniel Henrion
  11. Stefan Offermanns  Is a corresponding author
  1. Max Planck Institute for Heart and Lung Research, Germany
  2. University of Heidelberg, Germany
  3. UMR CNRS 6015 - INSERM 1083, Université d'Angers, France
  4. University of Regensburg, Germany

Abstract

Myogenic vasoconstriction is an autoregulatory function of small arteries. Recently, G-protein-coupled receptors have been involved in myogenic vasoconstriction, but the downstream signalling mechanisms and the in-vivo-function of this myogenic autoregulation are poorly understood. Here, we show that small arteries from mice with smooth muscle-specific loss of G12/G13 or the Rho guanine nucleotide exchange factor ARHGEF12 have lost myogenic vasoconstriction. This defect was accompanied by loss of RhoA activation, while vessels showed normal increases in intracellular [Ca2+]. In the absence of myogenic vasoconstriction, perfusion of peripheral organs was increased, systemic vascular resistance was reduced and cardiac output and left ventricular mass were increased. In addition, animals with defective myogenic vasoconstriction showed aggravated hypotension in response to endotoxin. We conclude that G12/G13- and Rho-mediated signaling plays a key role in myogenic vasoconstriction and that myogenic tone is required to maintain local and systemic vascular resistance under physiological and pathological condition.

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 Figures 1-5.

Article and author information

Author details

  1. Ramesh Chennupati

    Department of Pharmacology, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
    Competing interests
    The authors declare that no competing interests exist.
  2. Angela Wirth

    Institute of Pharmacology, University of Heidelberg, Heidelberg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  3. Julie Favre

    Laboratoire MITOVASC, UMR CNRS 6015 - INSERM 1083, Université d'Angers, Angers, France
    Competing interests
    The authors declare that no competing interests exist.
  4. Rui Li

    Department of Pharmacology, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
    Competing interests
    The authors declare that no competing interests exist.
  5. Rémy Bonnavion

    Department of Pharmacology, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
    Competing interests
    The authors declare that no competing interests exist.
  6. Young-June Jin

    Department of Pharmacology, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
    Competing interests
    The authors declare that no competing interests exist.
  7. Astrid Wietelmann

    Scientific Service Group Nuclear Magnetic Resonance Imaging, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
    Competing interests
    The authors declare that no competing interests exist.
  8. Frank Schweda

    Institute of Physiology, University of Regensburg, Regensburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  9. Nina Wettschureck

    Department of Pharmacology, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
    Competing interests
    The authors declare that no competing interests exist.
  10. Daniel Henrion

    Laboratoire MITOVASC, UMR CNRS 6015 - INSERM 1083, Université d'Angers, Angers, France
    Competing interests
    The authors declare that no competing interests exist.
  11. Stefan Offermanns

    Department of Pharmacology, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
    For correspondence
    stefan.offermanns@mpi-bn.mpg.de
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8676-6805

Funding

Max-Planck-Gesellschaft (Open-access funding)

  • Stefan Offermanns

This study was funded by the Max Planck Society.

Ethics

Animal experimentation: All animal care and use procedures in this study were approved by the local authorities (protocol numbers: B2-1031, B2-1166, B2-1069 Regierungspräsidia Karlsruhe and Darmstadt).

Reviewing Editor

  1. Mark T Nelson, University of Vermont, United States

Version history

  1. Received: June 16, 2019
  2. Accepted: September 24, 2019
  3. Accepted Manuscript published: September 24, 2019 (version 1)
  4. Version of Record published: October 4, 2019 (version 2)

Copyright

© 2019, Chennupati 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. Ramesh Chennupati
  2. Angela Wirth
  3. Julie Favre
  4. Rui Li
  5. Rémy Bonnavion
  6. Young-June Jin
  7. Astrid Wietelmann
  8. Frank Schweda
  9. Nina Wettschureck
  10. Daniel Henrion
  11. Stefan Offermanns
(2019)
Myogenic vasoconstriction requires G12/G13 and LARG to maintain local and systemic vascular resistance
eLife 8:e49374.
https://doi.org/10.7554/eLife.49374

Share this article

https://doi.org/10.7554/eLife.49374

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