title: FGF regulates TGF-β signaling and endothelial-to-mesenchymal transition via control of let-7 miRNA expression.
abstract: Maintenance of normal endothelial function is critical to various aspects of blood vessel function, but its regulation is poorly understood. In this study, we show that disruption of baseline fibroblast growth factor (FGF) signaling to the endothelium leads to a dramatic reduction in let-7 miRNA levels that, in turn, increases expression of transforming growth factor (TGF)-β ligands and receptors and activation of TGF-β signaling, leading to endothelial-to-mesenchymal transition (Endo-MT). We also find that Endo-MT is an important driver of neointima formation in a murine transplant arteriopathy model and in rejection of human transplant lesions. The decline in endothelial FGF signaling input is due to the appearance of an FGF resistance state that is characterized by inflammation-dependent reduction in expression and activation of key components of the FGF signaling cascade. These results establish FGF signaling as a critical factor in maintenance of endothelial homeostasis and point to an unexpected role of Endo-MT in vascular pathology.
authors.affiliation: Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Pei-Yu
authors.initials: PY
authors.lastname: Chen
authors.forename: Lingfeng
authors.initials: L
authors.lastname: Qin
authors.forename: Carmen
authors.initials: C
authors.lastname: Barnes
authors.forename: Klaus
authors.initials: K
authors.lastname: Charisse
authors.forename: Tai
authors.initials: T
authors.lastname: Yi
authors.forename: Xinbo
authors.initials: X
authors.lastname: Zhang
authors.forename: Rahmat
authors.initials: R
authors.lastname: Ali
authors.forename: Pedro P
authors.initials: PP
authors.lastname: Medina
authors.forename: Jun
authors.initials: J
authors.lastname: Yu
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Slack
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Anderson
authors.forename: Victor
authors.initials: V
authors.lastname: Kotelianski
authors.forename: Fen
authors.initials: F
authors.lastname: Wang
authors.forename: George
authors.initials: G
authors.lastname: Tellides
authors.forename: Michael
authors.initials: M
authors.lastname: Simons
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004727:Endothelium / Q000378:metabolism* / Q000473:pathology; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics; D058426:Neointima / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D014657:Vasculitis / Q000235:genetics / Q000378:metabolism / Q000473:pathology
chemical_list: D035683:MicroRNAs; D016212:Transforming Growth Factor beta; C487931:mirnlet7 microRNA, human; C542687:mirnlet7 microRNA, mouse; D005346:Fibroblast Growth Factors