EDN1 and systemic sclerosis: Given that a pro-fibrotic phenotype of SSc fibroblasts is largely due to stimulation by autocrine TGF-β, a potent inducer of ET-1, and those cells produce a much larger amount of ET-1 than normal dermal fibroblasts [1,7,38], it was speculated that the blockade of ET-1-dependent signaling by bosentan reverses the pro-fibrotic phenotype of SSc dermal fibroblasts by increasing the DNA binding of Fli1 through the inhibition of the c-Abl /PKC-δ/Fli1 pathway, which is constitutively activated in those cells [33].