FGF Regulates TGF-β Signaling and Endothelial-to-Mesenchymal Transition via Control of let-7 miRNA Expression

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. [Display omitted] ► FGF controls let-7 miRNA expression in endothelial cells ► A reduction in let-7 expression leads to endothelial-to-mesenchymal transition (Endo-MT) ► Endo-MT is an important contributor to human disease pathology Maintenance of normal endothelial homeostasis is critical to blood vessel function. In this study, Simon and colleagues demonstrate that disruption of fibroblast growth factor (FGF) signaling input to the endothelium reduces let-7 miRNA levels and activates TGF-β signaling, leading to endothelial-to-mesenchymal transition (Endo-MT). Endo-MT is an important driver of neointima formation in a number of animal models and in rejection of human transplant lesions. These results establish FGF signaling as a critical factor in maintenance of vascular homeostasis and point to an unexpected role of Endo-MT in vascular pathology.