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

Abstract

Summary 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 FGF signaling to the endothelium leads to a dramatic reduction in let-7 miRNA levels that in turns increases expression of TGFβ ligands and receptors and activation of TGFβ signaling leading to endothelial-to-mesenchymal transition (Endo-MT). We further find that Endo-MT is an important driver of neointima formation in a murine transplant arteriopathy model and in rejecting human transplants 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.

miR-99a/100∼125b tricistrons regulate hematopoietic stem and progenitor cell homeostasis by shifting the balance between TGFβ and Wnt signaling

“…miR-125 isoforms can also repress SMAD4 in human ESCs to favor neural commitment during neural conversion (Boissart et al 2012). let-7 family members inhibit TGFBR1 to prevent endothelial-to-mesenchymal transition, while, in chicken embryos, down-regulation of let-7 permits active ACVR2 to contribute to gastrulation (Bobbs et al 2012;Chen et al 2012).…”

Transforming Growth Factor β1 (TGF-β1) Enhances Expression of Profibrotic Genes through a Novel Signaling Cascade and MicroRNAs in Renal Mesangial Cells

“…Thus, the expression levels of let-7 and Lin28 are inversely correlated (29). Recently, it was found that under normal conditions, let-7 maintains low levels of TGF-␤R1 expression in human umbilical vein endothelial cells and in adult human liver cells (30,31). In addition, in tubular epithelial cells, lipoxins were shown to down-regulate TGF-␤R1-induced fibrosis by up-regulating let-7c (32).…”

The docking protein FRS2α is a critical regulator of VEGF receptors signaling

“…Primary mouse endothelial cells were isolated from the heart, lung, and liver by using rat anti-mouse CD31 antibody (clone MEC13.3, Pharmingen; 553370) and Dynabeads (catalog no. 110.35; Invitrogen) as described (25).…”

“…The lysates were centrifuged at 15,871 × g at 4°C for 15 min. The immunoprecipitation and Western blot analysis procedure were described (25).…”