{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T16:15:50Z","timestamp":1790007350411,"version":"4.0.1"},"reference-count":63,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"7","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["ATVB"],"published-print":{"date-parts":[[2023,7]]},"abstract":"<jats:sec>\n            <jats:title>Background:<\/jats:title>\n            <jats:p>The role of increased smooth muscle cell (SMC) integrin \u03b1v signaling in Marfan syndrome (MFS) aortic aneurysm remains unclear. Herein, we examine the mechanism and potential efficacy of integrin \u03b1v blockade as a therapeutic strategy to reduce aneurysm progression in MFS.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods:<\/jats:title>\n            <jats:p>\n              Induced pluripotent stem cells (iPSCs) were differentiated into aortic SMCs of the second heart field (SHF) and neural crest (NC) lineages, enabling in vitro modeling of MFS thoracic aortic aneurysms. The pathological role of integrin \u03b1v during aneurysm formation was confirmed by blockade of integrin \u03b1v with GLPG0187 in\n              <jats:italic>Fbn1<\/jats:italic>\n              <jats:sup>C1039G\/+<\/jats:sup>\n              MFS mice.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results:<\/jats:title>\n            <jats:p>\n              iPSC\u2013derived MFS SHF SMCs overexpress integrin \u03b1v relative to MFS NC and healthy control SHF cells. Furthermore, integrin \u03b1v downstream targets (FAK [focal adhesion kinase]\/Akt\n              <jats:sup>Thr308<\/jats:sup>\n              \/mTORC1 [mechanistic target of rapamycin complex 1]) were activated, especially in MFS SHF. Treatment of MFS SHF SMCs with GLPG0187 reduced p-FAK\/p-Akt\n              <jats:sup>Thr308<\/jats:sup>\n              \/mTORC1 activity back to control SHF levels. Functionally, MFS SHF SMCs had increased proliferation and migration compared to MFS NC SMCs and control SMCs, which normalized with GLPG0187 treatment. In the\n              <jats:italic>Fbn1<\/jats:italic>\n              <jats:sup>C1039G\/+<\/jats:sup>\n              MFS mouse model, integrin \u03b1v, p-Akt\n              <jats:sup>Thr308<\/jats:sup>\n              , and downstream targets of mTORC1 proteins were elevated in the aortic root\/ascending segment compared to littermate wild-type control. Mice treated with GLPG0187 (age 6\u201314 weeks) had reduced aneurysm growth, elastin fragmentation, and reduction of the FAK\/Akt\n              <jats:sup>Thr308<\/jats:sup>\n              \/mTORC1 pathway. GLPG0187 treatment reduced the amount and severity of SMC modulation assessed by single-cell RNA sequencing.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions:<\/jats:title>\n            <jats:p>\n              The integrin \u03b1v-FAK-Akt\n              <jats:sup>Thr308<\/jats:sup>\n              signaling pathway is activated in iPSC SMCs from MFS patients, specifically from the SHF lineage. Mechanistically, this signaling pathway promotes SMC proliferation and migration in vitro. As biological proof of concept, GLPG0187 treatment slowed aneurysm growth and p-Akt\n              <jats:sup>Thr308<\/jats:sup>\n              signaling in\n              <jats:italic>Fbn1<\/jats:italic>\n              <jats:sup>C1039G\/+<\/jats:sup>\n              mice. Integrin \u03b1v blockade via GLPG0187 may be a promising therapeutic approach to inhibit MFS aneurysmal growth.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/atvbaha.122.318448","type":"journal-article","created":{"date-parts":[[2023,4,20]],"date-time":"2023-04-20T09:08:41Z","timestamp":1681981721000},"page":"1134-1153","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":42,"title":["Lineage-Specific Induced Pluripotent Stem Cell\u2013Derived Smooth Muscle Cell Modeling Predicts Integrin Alpha-V Antagonism Reduces Aortic Root Aneurysm Formation in Marfan Syndrome Mice"],"prefix":"10.1161","volume":"43","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1293-7784","authenticated-orcid":true,"given":"Ken","family":"Nakamura","sequence":"first","affiliation":[{"name":"Department of Cardiothoracic Surgery (K.N., A.R.D., N.Y., A.J.P., S.K., O.M., C.G., B.M., M.L., W.H., 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