{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,1]],"date-time":"2026-03-01T16:37:47Z","timestamp":1772383067135,"version":"3.50.1"},"reference-count":35,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2015,4,27]],"date-time":"2015-04-27T00:00:00Z","timestamp":1430092800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"Ministry of Health, Labor, and Welfare of Japan"},{"name":"Japan Intractable Diseases Research Foundation"},{"name":"Rohto Dermatology Prize"},{"name":"Japanese Society for Investigative Dermatology Fellowship Shiseido Award"},{"DOI":"10.13039\/501100005865","name":"Mochida Memorial Foundation for Medical and Pharmaceutical Research","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100005865","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Actelion Academia Award"},{"name":"NIH","award":["AR-042334"],"award-info":[{"award-number":["AR-042334"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Arthritis &amp; Rheumatology"],"published-print":{"date-parts":[[2015,5]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>It is generally accepted that blockade of endothelin receptors has potentially beneficial effects on vasculopathy associated with systemic sclerosis (SSc). The aim of this study was to clarify the molecular mechanism underlying these effects using endothelial cell\u2013specific Fli\u20101\u2013knockout (Fli\u20101 ECKO) mice, an animal model of SSc vasculopathy.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Levels of messenger RNA for target genes and the expression and phosphorylation levels of target proteins were determined in human and murine dermal microvascular endothelial cells by real\u2010time quantitative reverse transcription\u2013polymerase chain reaction and immunoblotting, respectively. The binding of Fli\u20101 to the target gene promoters was evaluated using chromatin immunoprecipitation. Expression levels of Fli\u20101 and \u03b1\u2010smooth muscle actin in murine skin were evaluated using immunohistochemistry. Vascular structure and permeability were evaluated in mice injected with fluorescein isothiocyanate\u2013dextran and Evans blue dye, respectively.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In human dermal microvascular endothelial cells, endothelin 1 induced phosphorylation of Fli\u20101 at Thr<jats:sup>312<\/jats:sup> through the sequential activation of c\u2010Abl and protein kinase C\u03b4, leading to a decrease in Fli\u20101 protein levels as well as a decrease in binding of Fli\u20101 to the target gene promoters, whereas bosentan treatment reversed those effects. In Fli\u20101 ECKO mice, 4 weeks of treatment with bosentan increased endothelial Fli\u20101 expression, resulting in vascular stabilization and the restoration of impaired leaky vessels.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>The vascular fragility of Fli\u20101 ECKO mice was improved by bosentan through the normalization of Fli\u20101 protein levels and activity in endothelial cells, which may explain, in part, the mechanism underlying the beneficial effects of endothelin receptor blockade on SSc vasculopathy.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.39062","type":"journal-article","created":{"date-parts":[[2015,2,23]],"date-time":"2015-02-23T11:15:43Z","timestamp":1424690143000},"page":"1335-1344","source":"Crossref","is-referenced-by-count":28,"title":["Endothelin Receptor Blockade Ameliorates Vascular Fragility in Endothelial Cell\u2013Specific Fli\u20101\u2013Knockout Mice by Increasing Fli\u20101 DNA Binding 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