Triazole RGD antagonist reverts TGFβ1-induced endothelial-to-mesenchymal transition in endothelial precursor cells

Fibrosis is the dramatic consequence of a dysregulated reparative process in which activated fibroblasts (myofibroblasts) and Transforming Growth Factor 1 (TGF1) play a central role. When exposed to TGF1, fibroblast and epithelial cells differentiate in myofibroblasts, in addition, endothelial cells may undergo endothelial to mesenchymal transition (EndoMT) and actively participate to the progression of fibrosis. Recently, the role of v integrins, which recognize the Arg-Gly-Asp-(RGD) tripeptide, in the release and signal transduction activation of TGF1 became evident. Here we present a class of triazole-derived RGD-antagonists that interacts with v3 integrin. Above different compounds the RGD-2 specifically interferes with integrin-dependent TGF1 EndoMT in Endothelial Colony Forming Cells (ECPCs ) derived from circulating Endothelial Precursor Cells (ECPCs). The RGD-2 decreases the amount of membrane associated TGF1, and reduces both ALK5/TGF1 type I receptor expression and Smad2 phosphorylation in ECPCs. We found that RGD-2 antagonist reverts EndoMT, reducing -smooth muscle actin (-SMA) and vimentin expression in differentiated ECPCs. Our results outline the critical role of integrin in fibrosis progression and account for the opportunity of using integrins as target for anti-fibrotic therapeutic treatment.