Dysfunctional ERG signaling drives pulmonary vascular aging and persistent fibrosis

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 K. Huang, Roberto F. Nicosia, Daniel J. Tschumperlin, Maria Trojanowska and Giovanni Ligresti ()
Additional contact information
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

Nature Communications, 2022, vol. 13, issue 1, 1-19

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-31890-4

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