The SWELL1-LRRC8 complex regulates endothelial AKT-eNOS signaling and vascular function

  1. Ahmad F Alghanem
  2. Javier Abello
  3. Joshua M Maurer
  4. Ashutosh Kumar
  5. Chau My Ta
  6. Susheel K Gunasekar
  7. Urooj Fatima
  8. Chen Kang
  9. Litao Xie
  10. Oluwaseun Adeola
  11. Megan Riker
  12. Macaulay Elliot-Hudson
  13. Rachel A Minerath
  14. Chad E Grueter
  15. Robert F Mullins
  16. Amber N Stratman
  17. Rajan Sah  Is a corresponding author
  1. Washington University School of Medicine, United States
  2. Washington University, United States
  3. University of Iowa, United States
  4. Washington University in St. Louis, United States

Abstract

The endothelium responds to numerous chemical and mechanical factors in regulating vascular tone, blood pressure and blood flow. The endothelial volume regulatory anion channel (VRAC) has been proposed to be mechano-sensitive and thereby sense fluid flow and hydrostatic pressure to regulate vascular function. Here, we show that the Leucine Rich Repeat Containing Protein 8a, LRRC8A (SWELL1) is required for VRAC in human umbilical vein endothelial cells (HUVECs). Endothelial LRRC8A regulates AKT-eNOS signaling under basal, stretch and shear-flow stimulation, forms a GRB2-Cav1-eNOS signaling complex, and is required for endothelial cell alignment to laminar shear flow. Endothelium-restricted Lrrc8a KO mice develop hypertension in response to chronic angiotensin-II infusion and exhibit impaired retinal blood flow with both diffuse and focal blood vessel narrowing in the setting of Type 2 diabetes (T2D). These data demonstrate that LRRC8A regulates AKT-eNOS in endothelium and is required for maintaining vascular function, particularly in the setting of T2D.

Data availability

RNA sequencing data has been deposited in GEO under accession number GSE166989. All other data available as source data files.

The following data sets were generated

Article and author information

Author details

  1. Ahmad F Alghanem

    Department of Internal Medicine, Cardiovascular Division, Washington University School of Medicine, St. Louis, MO, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Javier Abello

    Department of Internal Medicine, Cardiovascular Division, Washington University, St. Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Joshua M Maurer

    Department of Internal Medicine, Cardiovascular Division, Washington University, St. Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Ashutosh Kumar

    Department of Internal Medicine, Cardiovascular Division, Washington University, St. Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Chau My Ta

    Department of Internal Medicine, Cardiovascular Division, Washington University School of Medicine, St. Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Susheel K Gunasekar

    Department of Internal Medicine, Cardiovascular Division, Washington University, St. Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Urooj Fatima

    Department of Internal Medicine, Cardiovascular Division, University of Iowa, Iowa City, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Chen Kang

    Department of Internal Medicine, Cardiovascular Division, Washington University, St. Louis, MO, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Litao Xie

    Department of Internal Medicine, Cardiovascular Division, Washington University, St. Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Oluwaseun Adeola

    Department of Internal Medicine, Cardiovascular Division, University of Iowa, Iowa City, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Megan Riker

    Department of Ophthalmology, University of Iowa, Carver College of Medicine, University of Iowa, Iowa City, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Macaulay Elliot-Hudson

    Department of Internal Medicine, Cardiovascular Division, University of Iowa, Iowa City, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Rachel A Minerath

    Fraternal Order of Eagles Diabetes Research Center, Division of Cardiology, University of Iowa, Iowa city, United States
    Competing interests
    The authors declare that no competing interests exist.
  14. Chad E Grueter

    Fraternal Order of Eagles Diabetes Research Center,Division of Cardiology, University of Iowa, Iowa city, United States
    Competing interests
    The authors declare that no competing interests exist.
  15. Robert F Mullins

    Department of Ophthalmology and Visual, University of Iowa, Iowa City, United States
    Competing interests
    The authors declare that no competing interests exist.
  16. Amber N Stratman

    Washington University in St. Louis, St. Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  17. Rajan Sah

    Department of Internal Medicine, Cardiovascular Division, Washington University, St. Louis, United States
    For correspondence
    rajan.sah@wustl.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1092-1244

Funding

National Institute of Diabetes and Digestive and Kidney Diseases (R01DK106009)

  • Rajan Sah

National Heart, Lung, and Blood Institute (5R00HL125683)

  • Amber N Stratman

National Heart, Lung, and Blood Institute (R01 HL125436)

  • Chad E Grueter

National Heart, Lung, and Blood Institute (R35 GM137976)

  • Amber N Stratman

VA Merit Award (I01BX005072)

  • Rajan Sah

King Abdullah International Medical Research Center (RA17-014-A)

  • Ahmad F Alghanem

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

Ethics

Animal experimentation: Animal experimentation: This study was performed in accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to the approved institutional animal care and use committee (IACUC) protocols of Washington University in St. Louis (20180217) and the University of Iowa (1308148).

Reviewing Editor

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

Publication history

  1. Received: July 22, 2020
  2. Accepted: February 22, 2021
  3. Accepted Manuscript published: February 25, 2021 (version 1)
  4. Version of Record published: March 19, 2021 (version 2)

Copyright

© 2021, Alghanem 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. Ahmad F Alghanem
  2. Javier Abello
  3. Joshua M Maurer
  4. Ashutosh Kumar
  5. Chau My Ta
  6. Susheel K Gunasekar
  7. Urooj Fatima
  8. Chen Kang
  9. Litao Xie
  10. Oluwaseun Adeola
  11. Megan Riker
  12. Macaulay Elliot-Hudson
  13. Rachel A Minerath
  14. Chad E Grueter
  15. Robert F Mullins
  16. Amber N Stratman
  17. Rajan Sah
(2021)
The SWELL1-LRRC8 complex regulates endothelial AKT-eNOS signaling and vascular function
eLife 10:e61313.
https://doi.org/10.7554/eLife.61313

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