title: Synergistic Role of Endothelial ERG and FLI1 in Mediating Pulmonary Vascular Homeostasis.
abstract: Endothelial cell (EC) activation underlies many vascular diseases, including pulmonary arterial hypertension (PAH). Several members of the E-twenty six (ETS) family of transcription factors are important regulators of the gene network governing endothelial homeostasis, and their aberrant expression is associated with pathological angiogenesis. The goal of this study was to determine whether deficiencies of the ETS family member, Friend leukemia integration 1 transcription factor (FLI1), and its closest homolog, ETS-related gene (ERG), are associated with PAH. We found that endothelial ERG was significantly reduced in the lung samples from patients with PAH, as well as in chronically hypoxic mice. Functional studies revealed that depletion of ERG or FLI1 in human pulmonary ECs led to increased expression of inflammatory genes, including IFN genes, whereas genes regulating endothelial homeostasis and cell-cell adhesion were down-regulated. Simultaneous knockdown of both ERG and FLI1 had synergistic or additive effects on the expression of these genes, suggesting that ERG and FLI1 coregulate at least a subset of their target genes. Functionally, knockdown of ERG and FLI1 induced cell monolayer permeability with a potency similar to that of vascular endothelial growth factor. Notably, stimulation of ECs with Toll-like receptor 3 ligand poly(I:C) suppressed ERG expression and induced ERG dissociation from the IFNB1 promoter, while promoting signal transducers and activators of transcription 1 (STAT1) recruitment. Consistent with the up-regulation of inflammatory genes seen in vitro, Erg and Fli1 double-heterozygote mice showed increased immune cell infiltration and expression of cytokines in the lung. In conclusion, loss of ERG and FLI1 might contribute to the pathogenesis of vascular lung complications through the induction of inflammation.
authors.affiliation: 1 Boston University School of Medicine, Arthritis Center/Rheumatology, Boston, Massachusetts; and.
authors.forename: Agnieszka P
authors.initials: AP
authors.lastname: Looney
authors.affiliation: 1 Boston University School of Medicine, Arthritis Center/Rheumatology, Boston, Massachusetts; and.
authors.forename: Rong
authors.initials: R
authors.lastname: Han
authors.affiliation: 1 Boston University School of Medicine, Arthritis Center/Rheumatology, Boston, Massachusetts; and.
authors.forename: Lukasz
authors.initials: L
authors.lastname: Stawski
authors.affiliation: 1 Boston University School of Medicine, Arthritis Center/Rheumatology, Boston, Massachusetts; and.
authors.forename: Grace
authors.initials: G
authors.lastname: Marden
authors.affiliation: 2 Orthopaedic Research, The Children's Hospital of Philadelphia Research Institute, Philadelphia, Pennsylvania.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Iwamoto
authors.affiliation: 1 Boston University School of Medicine, Arthritis Center/Rheumatology, Boston, Massachusetts; and.
authors.forename: Maria
authors.identifier: 0000-0001-9550-7178
authors.initials: M
authors.lastname: Trojanowska
mesh_terms: D000818:Animals; D002908:Chronic Disease; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006579:Heterozygote; D006706:Homeostasis / Q000187:drug effects / Q000235:genetics; D006801:Humans; D006976:Hypertension, Pulmonary / Q000150:complications / Q000235:genetics / Q000473:pathology; D000860:Hypoxia / Q000150:complications / Q000235:genetics / Q000473:pathology; D016899:Interferon-beta / Q000235:genetics; D008168:Lung / Q000098:blood supply* / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D011014:Pneumonia / Q000150:complications / Q000235:genetics / Q000473:pathology; D011070:Poly I-C / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000235:genetics; D051789:Proto-Oncogene Protein c-fli-1 / Q000235:genetics / Q000378:metabolism*; D011651:Pulmonary Artery / Q000473:pathology; D050794:STAT1 Transcription Factor / Q000378:metabolism; D000071230:Transcriptional Regulator ERG / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
chemical_list: C072312:ERG protein, human; C531115:ERG protein, mouse; D015513:Oncogene Proteins; D051789:Proto-Oncogene Protein c-fli-1; D050794:STAT1 Transcription Factor; D000071230:Transcriptional Regulator ERG; D016899:Interferon-beta; D011070:Poly I-C
keywords: E–twenty six–related gene; Friend leukemia integration 1 transcription factor; IFN; pulmonary arterial hypertension; systemic sclerosis