Cooperative ETS transcription factors enforce adult endothelial cell fate and cardiovascular homeostasis

Jesus M. Gomez-Salinero, Tomer Itkin, Sean Houghton, Chaitanya Badwe, Yang Lin, Viktoria Kalna, Neil Dufton, Claire R. Peghaire, Masataka Yokoyama, Matthew Wingo, Tyler M. Lu, Ge Li, Jenny Zhaoying Xiang, Yen Michael Sheng Hsu, David Redmond, Ryan Schreiner, Graeme M. Birdsey, Anna M. Randi, Shahin Rafii

Research output: Contribution to journalArticlepeer-review

Abstract

Current dogma dictates that, during adulthood, endothelial cells (ECs) are locked in an immutable stable homeostatic state. By contrast, herein we show that maintenance of EC fate and function are linked and active processes, which depend on the constitutive cooperativity of only two ETS transcription factors (TFs), ERG and Fli1. Although deletion of either ERG or Fli1 manifests subtle vascular dysfunction, their combined genetic deletion in adult ECs results in acute vasculopathy and multi-organ failure, due to loss of EC fate and integrity, hyperinflammation and spontaneous thrombosis, leading to death. ERG and Fli1 co-deficiency causes rapid transcriptional silencing of pan and organotypic vascular core genes, with dysregulation of inflammation and coagulation pathways. Vascular hyperinflammation leads to impaired hematopoiesis with myeloid skewing. Accordingly, enforced ERG and FLI1 expression in adult human mesenchymal stromal cells activates vascular programs and functionality, enabling in vivo engraftment of a perfusable vascular network. Genome-wide association study analysis identified vascular diseases that are associated with FLI1/ERG mutations. Constitutive expression of ERG and Fli1 upholds EC fate, physiological function and resilience in adult vasculature, whereas their functional loss can contribute to systemic human diseases.

Original languageEnglish
Pages (from-to)882-899
Number of pages18
JournalNature Cardiovascular Research
Volume1
Issue number10
DOIs
StatePublished - Oct 2022
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine
  • Biochemistry, Genetics and Molecular Biology (miscellaneous)
  • Cell Biology
  • Medicine (miscellaneous)

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