{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:58:50Z","timestamp":1792789130682,"version":"4.5.0"},"reference-count":48,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T00:00:00Z","timestamp":1789948800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Additional Ventures Single Ventricle Research Fund and Single Ventricle Expansion Fund","award":["991414"],"award-info":[{"award-number":["991414"]}],"id":[{"id":"https:\/\/ror.org\/01jmvv781","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Congenital Heart Defect Coalition and Fred Lovejoy House-Staff Research and Education Fund","award":["85728"],"award-info":[{"award-number":["85728"]}]},{"name":"the German Cardiac Society","id":[{"id":"https:\/\/ror.org\/02p22ad51","id-type":"ROR","asserted-by":"crossref"}]},{"id":[{"id":"https:\/\/ror.org\/02p22ad51","id-type":"ROR","asserted-by":"publisher"}]},{"name":"German Heart Foundation\/German Foundation of Heart Research"},{"id":[{"id":"https:\/\/ror.org\/02yjb3a91","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Sonnenfeld Foundation","id":[{"id":"https:\/\/ror.org\/04z2zsa77","id-type":"ROR","asserted-by":"crossref"}]},{"id":[{"id":"https:\/\/ror.org\/04z2zsa77","id-type":"ROR","asserted-by":"publisher"}]},{"name":"German Academic Exchange Service","id":[{"id":"https:\/\/ror.org\/039djdh30","id-type":"ROR","asserted-by":"crossref"}]},{"id":[{"id":"https:\/\/ror.org\/039djdh30","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Marietta Blau scholarship of the Austria\u2019s Agency for Education and Internationalisation"},{"name":"Austrian Marshall Plan Foundation","id":[{"id":"https:\/\/ror.org\/01ar4tp47","id-type":"ROR","asserted-by":"crossref"}]},{"id":[{"id":"https:\/\/ror.org\/01ar4tp47","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Children"],"abstract":"<jats:p>Background: Pulmonary vein stenosis (PVS) is a progressive disease characterized by neointimal hyperplasia with poor outcomes. Clinical observations show that adjunctive therapy with imatinib mesylate and sirolimus is associated with improved survival and reduced rates of reintervention. In this study, we aimed to investigate the cellular mechanisms underlying PVS development and progression and to elucidate how these targeted therapies modulate these processes. Methods: We retrospectively analyzed cardiac catheterization and computed tomography, and lung scan data from three patients with PVS to estimate wall shear stress (WSS) at multiple time points. Tissue specimens resected during anatomical repair surgery were analyzed for tissue composition and fibrosis using hematoxylin and eosin staining, Masson\u2019s trichrome staining, and flow cytometric analysis of endothelial cell (ECs) and fibroblast markers to determine endothelial-to-mesenchymal transition (EndMT). The safety and efficacy of imatinib mesylate and sirolimus were evaluated in healthy and PVS-derived ECs using cellular viability and proliferation assays, and by assessing fibrotic marker expression indicative of EndMT. Results: Patients exhibited severely elevated WSS estimates at multiple time points throughout disease progression. Disproportionate fibrotic remodeling driven by ECs transitioning into mesenchymal cells through EndMT was the cellular substrate of resected tissue in PVS. Targeted therapy with clinically relevant concentrations of imatinib mesylate and sirolimus was safe and significantly inhibited fibroproliferation and EndMT. At follow-up, all patients were alive and free of surgical and stent-based reintervention after anatomic repair surgery and adjunctive imatinib mesylate and sirolimus therapy. Conclusions: Fibroproliferative ECs undergoing EndMT are likely the cellular substrate underlying PVS development and progression. A multimodal approach consisting of anatomically focused surgical repair with adjunctive imatinib mesylate and sirolimus therapy may attenuate fibroproliferative remodeling.<\/jats:p>","DOI":"10.3390\/children13091280","type":"journal-article","created":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T09:01:38Z","timestamp":1789981298000},"page":"1280","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Imatinib Mesylate and Sirolimus Inhibit Vascular Fibroproliferative Remodeling in Pulmonary Vein Stenosis"],"prefix":"10.3390","volume":"13","author":[{"given":"Julia","family":"Gaal","sequence":"first","affiliation":[{"name":"Department of Cardiac Surgery, Boston Children\u2019s Hospital, Boston, MA 02115, USA"},{"name":"Department of Congenital Heart Surgery-Pediatric Heart Surgery, German Heart Center, Charit\u00e9\u2014Universit\u00e4tsmedizin Berlin, 13353 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-9759-4425","authenticated-orcid":false,"given":"Sophie C.","family":"Doettl","sequence":"additional","affiliation":[{"name":"Department of Cardiac Surgery, Boston Children\u2019s Hospital, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"validation","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3022-6214","authenticated-orcid":false,"given":"Kerstin","family":"Saraci","sequence":"additional","affiliation":[{"name":"Department of Cardiac Surgery, Boston Children\u2019s Hospital, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"}]},{"given":"Cindy","family":"Zajac","sequence":"additional","affiliation":[{"name":"Department of Cardiac Surgery, Boston Children\u2019s Hospital, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"validation","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"Alexa","family":"von Mueffling","sequence":"additional","affiliation":[{"name":"Department of Cardiac Surgery, Boston Children\u2019s Hospital, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"validation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4151-2777","authenticated-orcid":false,"given":"Peter E.","family":"Hammer","sequence":"additional","affiliation":[{"name":"Department of Cardiac Surgery, Boston Children\u2019s Hospital, Boston, MA 02115, USA"},{"name":"Department of Surgery, Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"}]},{"given":"Magnus","family":"von Piechowski","sequence":"additional","affiliation":[{"name":"Department of Cardiac Surgery, Boston Children\u2019s Hospital, Boston, MA 02115, USA"},{"name":"Department of Congenital Heart Surgery-Pediatric Heart Surgery, German Heart Center, Charit\u00e9\u2014Universit\u00e4tsmedizin Berlin, 13353 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"}]},{"given":"Verena","family":"Gebert","sequence":"additional","affiliation":[{"name":"Department of Cardiac Surgery, Boston Children\u2019s Hospital, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"data-curation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"Andrei-Antonio M.","family":"Caracioni","sequence":"additional","affiliation":[{"name":"Department of Cardiac Surgery, Boston Children\u2019s Hospital, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"Daniel","family":"Diaz-Gil","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Boston Children\u2019s Hospital, Boston, MA 02115, USA"},{"name":"Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"}]},{"given":"Viktoria","family":"Weixler","sequence":"additional","affiliation":[{"name":"Department of Congenital Heart Surgery-Pediatric Heart Surgery, German Heart Center, Charit\u00e9\u2014Universit\u00e4tsmedizin Berlin, 13353 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"}]},{"given":"Pedro J.","family":"Del Nido","sequence":"additional","affiliation":[{"name":"Department of Cardiac Surgery, Boston Children\u2019s Hospital, Boston, MA 02115, USA"},{"name":"Department of Surgery, Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8702-988X","authenticated-orcid":false,"given":"Kathy","family":"Jenkins","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Boston Children\u2019s Hospital, Boston, MA 02115, USA"},{"name":"Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2631-2972","authenticated-orcid":false,"given":"Ingeborg","family":"Friehs","sequence":"additional","affiliation":[{"name":"Department of Cardiac Surgery, Boston Children\u2019s Hospital, Boston, MA 02115, USA"},{"name":"Department of Surgery, Harvard Medical School, Boston, MA 02115, 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