{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T05:42:15Z","timestamp":1792820535659,"version":"4.5.0"},"reference-count":41,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"9","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2025,5,6]]},"abstract":"<jats:sec xml:lang=\"en\">\n                    <jats:title>Background<\/jats:title>\n                    <jats:p xml:lang=\"en\">Marfan syndrome (MFS) is a heritable connective tissue disorder caused by mutations in the Fibrillin\u20101 gene, which encodes the extracellular matrix protein fibrillin\u20101. Patients with MFS are predisposed to aortic aneurysms and dissections, significantly contributing to mortality. Emerging evidence suggests that endothelial cell (EC) senescence plays a critical role in the pathogenesis of aortic aneurysms in MFS. This study aims to elucidate the role of EC senescence in the development of aortic aneurysms in MFS using a vascular model derived from human induced pluripotent stem cells.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Methods and Results<\/jats:title>\n                    <jats:p xml:lang=\"en\">We generated human induced pluripotent stem cells lines from 2 patients with MFS carrying specific Fibrillin\u20101 mutations and differentiated these into ECs. These MFS\u2013hiPSC\u2010derived ECs were characterized using immunofluorescence, reverse transcription\u2010quantitative polymerase chain reaction, and Western blotting. Functional assays including cell proliferation, scratch wound, tube formation, NO content detection, and senescence\u2010associated \u03b2\u2010galactosidase staining were conducted. RNA sequencing was performed to elucidate underlying signaling pathways, and pharmacological inhibition of the transforming growth factor\u2010beta pathway was assessed for its therapeutic potential. MFS\u2013hiPSC\u2010derived ECs recapitulated the pathological features observed in Marfan aortas, particularly pronounced cellular senescence, decreased cell proliferation, and abnormal transforming growth factor\u2010beta and NF\u2010\u03baB signaling. These senescent ECs exhibited diminished proliferative and migratory capacities, reduced NO signaling, increased production of inflammatory cytokines, and attenuated responses to inflammatory stimuli. Importantly, senescence and dysfunction in MFS\u2010hiPSCderived ECs were ameliorated by transforming growth factor\u2010beta signaling pathway inhibitor, SB\u2010431542, suggesting a potential therapeutic strategy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p xml:lang=\"en\">This study highlights the pivotal role of endothelial cell senescence in the pathogenesis of aortic aneurysms in MFS. Our human induced pluripotent stem cells\u2013based disease model provides new insights into the disease mechanisms and underscores the potential of targeting the transforming growth factor\u2010beta pathway to mitigate endothelial dysfunction and senescence, offering a promising therapeutic avenue for MFS.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/jaha.124.037826","type":"journal-article","created":{"date-parts":[[2025,4,16]],"date-time":"2025-04-16T23:36:11Z","timestamp":1744846571000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":15,"title":["Endothelial Cell Senescence in Marfan Syndrome: Pathogenesis and Therapeutic Potential of TGF\u2010\u03b2 Pathway Inhibition"],"prefix":"10.1161","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-5222-5467","authenticated-orcid":false,"given":"Yuhao","family":"Chen","sequence":"first","affiliation":[{"name":"Wenzhou Medical University","place":["Zhejiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-8545-4658","authenticated-orcid":false,"given":"Yuankang","family":"Zhu","sequence":"additional","affiliation":[{"name":"Xinhua Hospital, Shanghai Jiao Tong University School of Medicine","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoli","family":"Ren","sequence":"additional","affiliation":[{"name":"Wenzhou Medical University","place":["Zhejiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1966-4080","authenticated-orcid":false,"given":"Lu","family":"Ding","sequence":"additional","affiliation":[{"name":"Wenzhou Medical University","place":["Zhejiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yubin","family":"Xu","sequence":"additional","affiliation":[{"name":"Wenzhou Medical University","place":["Zhejiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-9852-0726","authenticated-orcid":false,"given":"Miqi","family":"Zhou","sequence":"additional","affiliation":[{"name":"Wenzhou Medical University","place":["Zhejiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Runze","family":"Dong","sequence":"additional","affiliation":[{"name":"Wenzhou Medical University","place":["Zhejiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peifeng","family":"Jin","sequence":"additional","affiliation":[{"name":"The First Affiliated Hospital of Wenzhou Medical University","place":["Zhejiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiufang","family":"Chen","sequence":"additional","affiliation":[{"name":"Wenzhou Medical University","place":["Zhejiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaofang","family":"Fan","sequence":"additional","affiliation":[{"name":"Wenzhou Medical University","place":["Zhejiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7699-4502","authenticated-orcid":false,"given":"Ming","family":"Li","sequence":"additional","affiliation":[{"name":"Wenzhou Medical University","place":["Zhejiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongsheng","family":"Gong","sequence":"additional","affiliation":[{"name":"Wenzhou Medical University","place":["Zhejiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6088-8887","authenticated-orcid":false,"given":"Yongyu","family":"Wang","sequence":"additional","affiliation":[{"name":"Wenzhou Medical University","place":["Zhejiang, China"]},{"name":"Wenzhou Medical University","place":["Zhejiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41572-021-00298-7"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41436-020-01078-6"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2019.03.034"},{"key":"e_1_3_2_5_2","volume-title":"StatPearls [Internet]","author":"Salik I","year":"2025","unstructured":"Salik I, Rawla P. 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