Fibroblast growth factor receptor 1 is a key inhibitor of TGFβ signaling in the endothelium

Pei-Yu Chen; Lingfeng Qin; George Tellides; Michael Simons

doi:10.1126/scisignal.2005504

Fibroblast growth factor receptor 1 is a key inhibitor of TGFβ signaling in the endothelium

Sci Signal. 2014 Sep 23;7(344):ra90. doi: 10.1126/scisignal.2005504.

Authors

Pei-Yu Chen¹, Lingfeng Qin², George Tellides², Michael Simons³

Affiliations

¹ Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA. [email protected] [email protected].
² Department of Surgery, Yale University School of Medicine, New Haven, CT 06520, USA.
³ Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA. Department of Cell Biology, Yale University School of Medicine, New Haven, CT 06520, USA. [email protected] [email protected].

PMID: 25249657
DOI: 10.1126/scisignal.2005504

Abstract

Abnormal vascular homeostasis can lead to increased proliferation of smooth muscle cells and deposition of extracellular matrix, resulting in neointima formation, which contributes to vascular lumen narrowing, a pathology that underlies diseases including transplant vasculopathy, the recurrence of stenosis, and atherosclerosis. Growth of neointima is in part due to endothelial-to-mesenchymal transition (EndMT), a transforming growth factor-β (TGFβ)-driven process, which leads to increased numbers of smooth muscle cells and fibroblasts and deposition of extracellular matrix. We reported that endothelial cell-specific knockout of fibroblast growth factor receptor 1 (FGFR1) led to activation of TGFβ signaling and development of EndMT in vitro and in vivo. Furthermore, EndMT in human diseased vasculature correlated with decreased abundance of FGFR1. These findings identify FGFR1 as the key regulator of TGFβ signaling and EndMT development.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Animals
Cell Transdifferentiation
Coronary Vessels / metabolism
Coronary Vessels / pathology
Coronary Vessels / transplantation
Endothelium, Vascular / physiology*
Extracellular Matrix / metabolism
Fibroblasts / metabolism
Fibroblasts / pathology
Graft Rejection / pathology
Heart Transplantation
Heterografts
Hindlimb / blood supply
Human Umbilical Vein Endothelial Cells
Humans
Ischemia / metabolism
Mesoderm / cytology
Mice
Mice, Mutant Strains
MicroRNAs / metabolism
Muscle, Smooth, Vascular / pathology
Neointima / physiopathology*
Receptor, Fibroblast Growth Factor, Type 1 / deficiency
Receptor, Fibroblast Growth Factor, Type 1 / physiology*
Receptors, Fibroblast Growth Factor / antagonists & inhibitors
Signal Transduction / physiology*
Smad2 Protein / metabolism
Transforming Growth Factor beta / physiology*
Transplantation Chimera

Substances

MicroRNAs
Receptors, Fibroblast Growth Factor
SMAD2 protein, human
Smad2 Protein
Transforming Growth Factor beta
mirnlet7 microRNA, human
FGFR1 protein, human
Fgfr1 protein, mouse
Receptor, Fibroblast Growth Factor, Type 1

Grants and funding

R01 HL053793/HL/NHLBI NIH HHS/United States