@article{d8f750d2d7d444b09aa081b3fa13e03f,
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.",
author = "Chen, {Pei Yu} and Lingfeng Qin and Carmen Barnes and Klaus Charisse and Tai Yi and Xinbo Zhang and Rahmat Ali and Medina, {Pedro P.} and Jun Yu and Slack, {Frank J.} and Anderson, {Daniel G.} and Victor Kotelianski and Fen Wang and George Tellides and Michael Simons",
note = "Funding Information: We thank R. Friesel (Maine Medical Center Research Institute) for providing FGFR1 constructs and FGFR1 antibody, R. Adams (Max Planck Institute, Munster) for Cdh5-CreERT2 mouse, V. Eswarakumar (Yale University) for the gift of Frs2α-2F mice, N. Kirkiles-Smith (Yale University) for technical assistance with i.v. injections, B. McManus (University of British Columbia) for human coronary artery specimens, and S. Kuchimanchi (Alnylam) for miR mimics synthesis. This work was supported by National Institutes of Health Grants R01-HL 053793 (to M.S.) and R01-CA 131301 (to F.J.S.). P.-Y.C., L.Q., G.T., and M.S. conceived and designed the experiments and discussed the results. P.-Y.C., L.Q., T.Y., X.Z., R.A., and J.Y. performed experiments. P.P.M. and F.J.S. generated and provided let-7 sponge construct, F.W. generated Frs2 knockin mouse, and C.B., K.C., D.G.A., and V.K. developed in vivo delivery system and generated and provided let-7 anti-miRs for in vivo studies. P.-Y.C., G.T., and M.S. wrote the manuscript. C.B., K.C., and V.K. were employees of Alnylam, Inc. when this work was performed. ",
year = "2012",
month = dec,
day = "27",
doi = "10.1016/j.celrep.2012.10.021",
language = "English (US)",
volume = "2",
pages = "1684--1696",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "6",
}