000 02711 am a22004093u 4500
042 _adc
100 1 0 _aGomez-Salinero, Jesus M
_eauthor
_92545
700 1 0 _aItkin, Tomer
_eauthor
_92546
700 1 0 _aHoughton, Sean
_eauthor
_92547
700 1 0 _aBadwe, Chaitanya
_eauthor
_92548
700 1 0 _aLin, Yang
_eauthor
_92549
700 1 0 _aKalna, Viktoria
_eauthor
_92550
700 1 0 _aDufton, Neil
_eauthor
_92551
700 1 0 _aPeghaire, Claire R
_eauthor
_92552
700 1 0 _aYokoyama, Masataka
_eauthor
_92553
700 1 0 _aWingo, Matthew
_eauthor
_92554
700 1 0 _aLu, Tyler M.
_eauthor
_92555
700 1 0 _aLi, Ge
_eauthor
_92556
700 1 0 _aXiang, Jenny Zhaoying
_eauthor
_92557
700 1 0 _aHsu, Yen-Michael Sheng
_eauthor
_92558
700 1 0 _aRedmond, David
_eauthor
_92559
700 1 0 _aSchreiner, Ryan
_eauthor
_92560
700 1 0 _aBirdsey, Graeme M
_eauthor
_92561
700 1 0 _aRandi, Anna M
_eauthor
_92562
700 1 0 _aRafii, Shahin
_eauthor
_92563
245 0 0 _aCooperative ETS Transcription Factors Enforce Adult Endothelial Cell Fate and Cardiovascular Homeostasis
260 _c2022-10.
500 _a/pmc/articles/PMC7614113/
500 _a/pubmed/36713285
520 _aCurrent 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. While deletion of either Fli1 or ERG manifest subtle vascular dysfunction, their combined genetic deletion in adult EC results in acute vasculopathy and multiorgan failure, due to loss of EC fate and integrity, hyperinflammation, and spontaneous thrombosis, leading to death. ERG and Fli1 co-deficiency cause 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 engraftment of perfusable vascular network. GWAS-analysis identified vascular diseases are associated with FLI1/Erg mutations. Constitutive expression of ERG and Fli1 uphold EC fate, physiological function, and resilience in adult vasculature; while their functional loss can contribute to systemic human diseases.
540 _a
546 _aen
690 _aArticle
655 7 _aText
_2local
786 0 _nNat Cardiovasc Res
856 4 1 _uhttp://dx.doi.org/10.1038/s44161-022-00128-3
_zConnect to this object online.
999 _c933
_d933