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The transcription factor ERG regulates a low shear stress-induced anti-thrombotic pathway in the microvasculature

Author

Listed:
  • C. Peghaire

    (Imperial College London)

  • N. P. Dufton

    (Imperial College London)

  • M. Lang

    (Imperial College London)

  • I. I. Salles-Crawley

    (Imperial College London)

  • J. Ahnström

    (Imperial College London)

  • V. Kalna

    (Imperial College London)

  • C. Raimondi

    (Imperial College London)

  • C. Pericleous

    (Imperial College London)

  • L. Inuabasi

    (Imperial College London)

  • R. Kiseleva

    (University of Pennsylvania School of Medicine)

  • V. R. Muzykantov

    (University of Pennsylvania School of Medicine)

  • J. C. Mason

    (Imperial College London)

  • G. M. Birdsey

    (Imperial College London)

  • A. M. Randi

    (Imperial College London)

Abstract

Endothelial cells actively maintain an anti-thrombotic environment; loss of this protective function may lead to thrombosis and systemic coagulopathy. The transcription factor ERG is essential to maintain endothelial homeostasis. Here, we show that inducible endothelial ERG deletion (ErgiEC-KO) in mice is associated with spontaneous thrombosis, hemorrhages and systemic coagulopathy. We find that ERG drives transcription of the anticoagulant thrombomodulin (TM), as shown by reporter assays and chromatin immunoprecipitation. TM expression is regulated by shear stress (SS) via Krüppel-like factor 2 (KLF2). In vitro, ERG regulates TM expression under low SS conditions, by facilitating KLF2 binding to the TM promoter. However, ERG is dispensable for TM expression in high SS conditions. In ErgiEC-KO mice, TM expression is decreased in liver and lung microvasculature exposed to low SS but not in blood vessels exposed to high SS. Our study identifies an endogenous, vascular bed-specific anticoagulant pathway in microvasculature exposed to low SS.

Suggested Citation

  • C. Peghaire & N. P. Dufton & M. Lang & I. I. Salles-Crawley & J. Ahnström & V. Kalna & C. Raimondi & C. Pericleous & L. Inuabasi & R. Kiseleva & V. R. Muzykantov & J. C. Mason & G. M. Birdsey & A. M. , 2019. "The transcription factor ERG regulates a low shear stress-induced anti-thrombotic pathway in the microvasculature," Nature Communications, Nature, vol. 10(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-12897-w
    DOI: 10.1038/s41467-019-12897-w
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    Cited by:

    1. Nunzia Caporarello & Jisu Lee & Tho X. Pham & Dakota L. Jones & Jiazhen Guan & Patrick A. Link & Jeffrey A. Meridew & Grace Marden & Takashi Yamashita & Collin A. Osborne & Aditya V. Bhagwate & Steven, 2022. "Dysfunctional ERG signaling drives pulmonary vascular aging and persistent fibrosis," Nature Communications, Nature, vol. 13(1), pages 1-19, December.

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