FGF regulates TGF-β signaling and endothelial-to-mesenchymal transition via control of let-7 miRNA expression

Cell Rep. 2012 Dec 27;2(6):1684-96. doi: 10.1016/j.celrep.2012.10.021. Epub 2012 Nov 29.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Disease Models, Animal
  • Endothelium / metabolism*
  • Endothelium / pathology
  • Fibroblast Growth Factors / genetics
  • Fibroblast Growth Factors / metabolism*
  • Gene Expression Regulation*
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Mice, Transgenic
  • MicroRNAs / biosynthesis*
  • MicroRNAs / genetics
  • Neointima / genetics
  • Neointima / metabolism*
  • Neointima / pathology
  • Signal Transduction*
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta / metabolism*
  • Vasculitis / genetics
  • Vasculitis / metabolism
  • Vasculitis / pathology


  • MicroRNAs
  • Transforming Growth Factor beta
  • mirnlet7 microRNA, human
  • mirnlet7 microRNA, mouse
  • Fibroblast Growth Factors