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

Pei Yu Chen, Lingfeng Qin, Carmen Barnes, Klaus Charisse, Tai Yi, Xinbo Zhang, Rahmat Ali, Pedro P. Medina, Jun Yu, Frank J. Slack, Daniel G. Anderson, Victor Kotelianski, Fen Wang, George Tellides, Michael Simons

Research output: Contribution to journalArticlepeer-review

201 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1684-1696
Number of pages13
JournalCell Reports
Volume2
Issue number6
DOIs
StatePublished - Dec 27 2012

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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