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Dysfunctional ERG signaling drives pulmonary vascular aging and persistent fibrosis

Author

Listed:
  • Nunzia Caporarello

    (Mayo Clinic)

  • Jisu Lee

    (Boston University School of Medicine)

  • Tho X. Pham

    (Boston University School of Medicine)

  • Dakota L. Jones

    (University of Pennsylvania)

  • Jiazhen Guan

    (Boston University School of Medicine)

  • Patrick A. Link

    (Mayo Clinic)

  • Jeffrey A. Meridew

    (Mayo Clinic)

  • Grace Marden

    (Boston University School of Medicine)

  • Takashi Yamashita

    (Boston University School of Medicine)

  • Collin A. Osborne

    (Mayo Clinic)

  • Aditya V. Bhagwate

    (Mayo Clinic)

  • Steven K. Huang

    (University of Michigan Medical School)

  • Roberto F. Nicosia

    (University of Washington)

  • Daniel J. Tschumperlin

    (Mayo Clinic)

  • Maria Trojanowska

    (Boston University School of Medicine)

  • Giovanni Ligresti

    (Boston University School of Medicine)

Abstract

Vascular dysfunction is a hallmark of chronic diseases in elderly. The contribution of the vasculature to lung repair and fibrosis is not fully understood. Here, we performed an epigenetic and transcriptional analysis of lung endothelial cells (ECs) from young and aged mice during the resolution or progression of bleomycin-induced lung fibrosis. We identified the transcription factor ETS-related gene (ERG) as putative orchestrator of lung capillary homeostasis and repair, and whose function is dysregulated in aging. ERG dysregulation is associated with reduced chromatin accessibility and maladaptive transcriptional responses to injury. Loss of endothelial ERG enhances paracrine fibroblast activation in vitro, and impairs lung fibrosis resolution in young mice in vivo. scRNA-seq of ERG deficient mouse lungs reveales transcriptional and fibrogenic abnormalities resembling those associated with aging and human lung fibrosis, including reduced number of general capillary (gCap) ECs. Our findings demonstrate that lung endothelial chromatin remodeling deteriorates with aging leading to abnormal transcription, vascular dysrepair, and persistent fibrosis following injury.

Suggested Citation

  • 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.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-31890-4
    DOI: 10.1038/s41467-022-31890-4
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    1. Di-Yang Sun & Wen-Bin Wu & Jian-Jin Wu & Yu Shi & Jia-Jun Xu & Shen-Xi Ouyang & Chen Chi & Yi Shi & Qing-Xin Ji & Jin-Hao Miao & Jiang-Tao Fu & Jie Tong & Ping-Ping Zhang & Jia-Bao Zhang & Zhi-Yong Li, 2024. "Pro-ferroptotic signaling promotes arterial aging via vascular smooth muscle cell senescence," Nature Communications, Nature, vol. 15(1), pages 1-22, December.
    2. Ahmed A. Raslan & Tho X. Pham & Jisu Lee & Konstantinos Kontodimas & Andrew Tilston-Lunel & Jillian Schmottlach & Jeongmin Hong & Taha Dinc & Andreea M. Bujor & Nunzia Caporarello & Aude Thiriot & Ulr, 2024. "Lung injury-induced activated endothelial cell states persist in aging-associated progressive fibrosis," Nature Communications, Nature, vol. 15(1), pages 1-20, December.

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