Journal article
Dysfunctional ERG signaling drives pulmonary vascular aging and persistent fibrosis
Nature communications, Vol.13(1), 4170
07/25/2022
DOI: 10.1038/s41467-022-31890-4
PMCID: PMC9314350
PMID: 35879310
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.
Vascular dysfunction is associated with ageing and chronic diseases, but its role in lung repair and fibrosis is unclear. Here, the authors show that the endothelial transcription factor ERG is a mediator of vascular repair whose function declines in aged lungs resulting in sustained fibrosis
Details
- Title: Subtitle
- Dysfunctional ERG signaling drives pulmonary vascular aging and persistent fibrosis
- Creators
- Nunzia Caporarello - Mayo Clinic in FloridaJisu Lee - Boston UniversityTho X. Pham - Boston UniversityDakota L. Jones - University of PennsylvaniaJiazhen Guan - Boston UniversityPatrick A. Link - Mayo Clinic in FloridaJeffrey A. Meridew - Mayo Clinic in FloridaGrace Marden - Boston UniversityTakashi Yamashita - Boston UniversityCollin A. Osborne - Mayo Clinic in FloridaAditya V. Bhagwate - Mayo Clinic in FloridaSteven K. Huang - University of Michigan Medical SchoolRoberto F. Nicosia - University of WashingtonDaniel J. Tschumperlin - Mayo Clinic in FloridaMaria Trojanowska - Boston UniversityGiovanni Ligresti - Boston University
- Resource Type
- Journal article
- Publication Details
- Nature communications, Vol.13(1), 4170
- DOI
- 10.1038/s41467-022-31890-4
- PMID
- 35879310
- PMCID
- PMC9314350
- NLM abbreviation
- Nat Commun
- ISSN
- 2041-1723
- eISSN
- 2041-1723
- Publisher
- Nature Publishing Group UK
- Grant note
- HL007035; HL105355; HL105355; HL092961; HL150638; AR060780; HL142596 / U.S. Department of Health & Human Services | National Institutes of Health (NIH) (https://doi.org/10.13039/100000002) Dalsemer Award / American Lung Association (Lung Association) (https://doi.org/10.13039/100002590) IPF/ILD Discovery Award / Boehringer Ingelheim (Boehringer Ingelheim Pharmaceuticals) (https://doi.org/10.13039/100001003) U.S. Department of Health & Human Services | National Institutes of Health (NIH)
- Language
- English
- Date published
- 07/25/2022
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Anatomy and Cell Biology; Craniofacial Anomalies Research Center
- Record Identifier
- 9984948043402771
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