{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T04:46:20Z","timestamp":1791521180465,"version":"4.3.4"},"reference-count":50,"publisher":"The Journal of Rheumatology","issue":"10","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J Rheumatol"],"published-print":{"date-parts":[[2015,10]]},"abstract":"<jats:sec><jats:title>Objective.<\/jats:title><jats:p>High endothelin-1 (ET-1) and transforming growth factor-\u03b2 (TGF-\u03b2) levels may induce in healthy endothelial cells (EC) an endothelial-to-mesenchymal transition (EndMT). The same cytokines are associated with fibrosis development in systemic sclerosis (SSc). Although EndMT has not been definitively shown in SSc, this process, potentially induced by a stimulatory loop involving these 2 cytokines, overexpressed in this disease might contribute to fibroblast accumulation in affected tissues. Macitentan (MAC), an ET-1 receptor antagonist interfering with this loop, might prevent EndMT and fibroblast accumulation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods.<\/jats:title><jats:p>EC, isolated from healthy controls (HC) and patients with SSc, were treated with ET-1 and TGF-\u03b2 and successively analyzed for gene and protein expressions of endothelial and mesenchymal markers, and for Sma- and Mad-related (SMAD) phosphorylation. Further, in the supernatants, we evaluated ET-1 and TGF-\u03b2 production by ELISA assay. In each assay we evaluated the ability of MAC to inhibit both the TGF-\u03b2 and ET-1 effects.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results.<\/jats:title><jats:p>We showed that both TGF-\u03b2 and ET-1 treatments induced an activation of the EndMT process in SSc-EC as reported in HC cells. The ELISA assays showed a mutual TGF-\u03b2 and ET-1 induction in both SSc-EC and HC-EC. A statistically significant increase of SMAD phosphorylation after treatment was observed in SSc-EC. In each assay, MAC inhibited both TGF-\u03b2 and ET-1 effects.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion.<\/jats:title><jats:p>Our work is the first demonstration in literature that SSc-EC, under the synergistic effect of TGF-\u03b2 and ET-1, may transdifferentiate toward myofibroblasts, thus contributing to fibroblast accumulation. MAC, interfering with this process<jats:italic>in vitro<\/jats:italic>, may offer a new potential therapeutic strategy against fibrosis.<\/jats:p><\/jats:sec>","DOI":"10.3899\/jrheum.150088","type":"journal-article","created":{"date-parts":[[2015,8,15]],"date-time":"2015-08-15T23:58:42Z","timestamp":1439683122000},"page":"1808-1816","source":"Crossref","is-referenced-by-count":107,"title":["The Endothelial-mesenchymal Transition in Systemic Sclerosis Is Induced by Endothelin-1 and Transforming Growth Factor-\u03b2 and May Be Blocked by Macitentan, a Dual Endothelin-1 Receptor Antagonist"],"prefix":"10.3899","volume":"42","author":[{"given":"Paola","family":"Cipriani","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paola","family":"Di 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