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Inhibitors of mTOR improve clinical outcome of LAM patients by preventing loss of lung function. Nevertheless, other cell targets may be of interest for drug development. Therefore, we explored the potential role of EDN1 (endothelin) in LAM. We report an increased endothelin blood level in LAM patients as well as EDN1 overexpression and EDN1 receptor downregulation in LAM-derived primary cells and in TSC2<jats:sup>NEG<\/jats:sup> cells mutated in TSC2. We evidenced EDN pathway dysregulation based on EDN1, EDNRA, EDNRB and ARRB1 mRNA expression in LAM-derived primary cells. We showed overexpression of EDN1 and ARRB1 mRNAs in TSC2<jats:sup>NEG<\/jats:sup> cells; these cells lost their ability to respond to stimulation by endothelin. We analyzed the effects of endothelin receptor antagonists alone or in combination with rapamycin, an mTOR inhibitor, on proliferation and migration of LAM cells. Rapamycin treatment of TSC2<jats:sup>NEG<\/jats:sup> cells significantly reduced cell proliferation or migration, while none of the tested inhibitors of EDN receptors impaired these functions. We showed that TSC2<jats:sup>NEG<\/jats:sup> cells have acquired a transformed phenotype as showed by their ability to grow as spheroids in semi-solid medium and that unlike endothelin receptors antagonists, rapamycin reduced anchorage-independent cell growth and prevented expansion of TSC2<jats:sup>NEG<\/jats:sup> spheroids.<\/jats:p>","DOI":"10.1038\/s41598-018-32795-3","type":"journal-article","created":{"date-parts":[[2018,9,26]],"date-time":"2018-09-26T15:22:59Z","timestamp":1537975379000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Dysregulation of the endothelin pathway in lymphangioleiomyomatosis with no direct effect on cell proliferation and migration"],"prefix":"10.1038","volume":"8","author":[{"given":"Nader","family":"Chebib","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabienne","family":"Archer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra","family":"Bobet-Erny","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7923-3127","authenticated-orcid":false,"given":"Caroline","family":"Leroux","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincent","family":"Cottin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2018,10,2]]},"reference":[{"key":"32795_CR1","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1164\/rccm.200409-1298OC","volume":"173","author":"JH Ryu","year":"2006","unstructured":"Ryu, J. 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