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

ETS转录因子家族 飞行1 生物 转录因子 细胞生物学 基因沉默 间充质干细胞 Erg公司 细胞命运测定 癌症研究 免疫学 内皮功能障碍 条件基因敲除 内皮干细胞 遗传学 表型 内分泌学 基因 神经科学 体外 视网膜
作者
Jesús M. Gómez-Salinero,Tomer Itkin,Sean Houghton,Chaitanya R. Badwe,Yang Lin,Viktoria Kalna,Neil Dufton,Claire Peghaire,Masataka Yokoyama,Matthew Wingo,Tyler M. Lu,Ge Li,Jenny Xiang,Yen‐Michael S. Hsu,David Redmond,Ryan Schreiner,Graeme M. Birdsey,Anna M. Randi,Shahin Rafii
出处
期刊:Nature Cardiovascular Research [Springer Nature]
卷期号:1 (10): 882-899 被引量:9
标识
DOI:10.1038/s44161-022-00128-3
摘要

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. Gomez-Salinero, Itkin et al. demonstrate the cooperative role of two ETS transcriptor factors, ERG and Fli1, in the active maintenance of endothelial cell homeostatic function. Loss of these two genes in adult mice leads to multi-organ failure, hyperinflammation, systemic thrombosis and death. In vitro, expression of both ERG and FLI1 induces human adult non-vascular mesenchymal stromal cells to acquire endothelial-like properties. In humans, several cardiovascular disorders and inflammatory-related diseases are linked to mutations in both genes.
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