{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T02:41:10Z","timestamp":1788230470160,"version":"build-2803163510"},"reference-count":75,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"14","funder":[{"DOI":"10.13039\/501100000274","name":"British Heart Foundation","doi-asserted-by":"publisher","award":["PG\/12\/31\/2952"],"award-info":[{"award-number":["PG\/12\/31\/2952"]}],"id":[{"id":"10.13039\/501100000274","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004543","name":"China Scholarship Council","doi-asserted-by":"publisher","award":["201908500055"],"award-info":[{"award-number":["201908500055"]}],"id":[{"id":"10.13039\/501100004543","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Adv."],"published-print":{"date-parts":[[2026,4,3]]},"abstract":"<jats:p>\n                    <jats:italic toggle=\"yes\">NOTCH3<\/jats:italic>\n                    variants cause CADASIL (cerebral autosomal dominant arteriopathy and subcortical infarcts and leukoencephalopathy), the most common monogenetic form of small vessel disease (SVD) and vascular dementia (VaD). The molecular mechanisms driving CADASIL pathogenesis remain poorly understood, and no specific treatments are currently available.\n                    <jats:italic toggle=\"yes\">NOTCH3<\/jats:italic>\n                    is mainly expressed in vascular smooth muscle cells (VSMCs) that arise from different embryonic origins. Using human induced pluripotent stem cell (iPSC) models, we generated origin-specific VSMCs and found that cerebral, but not peripheral, VSMC mimics are selectively vulnerable to\n                    <jats:italic toggle=\"yes\">NOTCH3<\/jats:italic>\n                    variants. CADASIL iPSC\u2013derived brain-specific VSMCs acquired a synthetic phenotype, accompanied with extensive extracellular matrix accumulation and impaired cell adhesion leading to anoikis. Furthermore, an endothelial-independent nitric oxide signaling was substantially impaired in CADASIL iPSC\u2013derived VSMCs. Phosphodiesterase-5 inhibition successfully reversed the functional abnormality and survival of mutant VSMCs. Our findings uncovered mechanistic insights and suggest a viable therapeutic strategy for\n                    <jats:italic toggle=\"yes\">NOTCH3<\/jats:italic>\n                    -associated SVD\/VaD, reinforcing the value of patient-specific iPSCs for disease modeling and potential drug discovery.\n                  <\/jats:p>","DOI":"10.1126\/sciadv.aeb1134","type":"journal-article","created":{"date-parts":[[2026,4,3]],"date-time":"2026-04-03T17:58:57Z","timestamp":1775239137000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":3,"title":["Selective vulnerability of cerebral vasculature to\n                    <i>NOTCH3<\/i>\n                    variants in small vessel disease and rescue by phosphodiesterase-5 inhibitor"],"prefix":"10.1126","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-3769-2337","authenticated-orcid":true,"given":"Xiangjun","family":"Zhao","sequence":"first","affiliation":[{"name":"Division of Evolution, Infection and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine, and Health, The University of Manchester, Manchester, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chaowen","family":"Yu","sequence":"additional","affiliation":[{"name":"Division of Evolution, Infection and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine, and Health, The University of Manchester, Manchester, UK."},{"name":"Children\u2019s Hospital of Chongqing Medical University, Chongqing 400014, P.R. China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5408-0013","authenticated-orcid":true,"given":"Antony","family":"Adamson","sequence":"additional","affiliation":[{"name":"Genome Editing Unit, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aite","family":"Zhao","sequence":"additional","affiliation":[{"name":"College of Computer Science and Technology, Qingdao University, Qingdao, P.R. China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1634-9840","authenticated-orcid":true,"given":"Huiyu","family":"Zhou","sequence":"additional","affiliation":[{"name":"School of Computing and Mathematical Sciences, University of Leicester, Leicester, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pankaj","family":"Sharma","sequence":"additional","affiliation":[{"name":"Institute of Cardiovascular Research, Royal Holloway, University of London, Ashford and St Peter\u2019s NHS Foundation Trust, and Imperial College Healthcare NHS Trust, London, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3401-5131","authenticated-orcid":true,"given":"Tao","family":"Wang","sequence":"additional","affiliation":[{"name":"Division of Evolution, Infection and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine, and Health, The University of Manchester, Manchester, UK."},{"name":"Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Manchester, UK."},{"name":"Geoffrey Jefferson Brain Research Centre, Manchester Academic Health Science Centre, Northern Care Alliance and University of Manchester, Manchester, 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Schiele Learning non-maximum suppression in Proceedings of the IEEE Conference on Computer Vision and Pattern Recognition (IEEE 2017) pp. 6469\u20136477.","DOI":"10.1109\/CVPR.2017.685"},{"key":"e_1_3_2_76_2","doi-asserted-by":"publisher","DOI":"10.1109\/4.996"}],"container-title":["Science Advances"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.science.org\/doi\/pdf\/10.1126\/sciadv.aeb1134","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,3]],"date-time":"2026-04-03T17:59:54Z","timestamp":1775239194000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.science.org\/doi\/10.1126\/sciadv.aeb1134"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,3]]},"references-count":75,"journal-issue":{"issue":"14","published-print":{"date-parts":[[2026,4,3]]}},"alternative-id":["10.1126\/sciadv.aeb1134"],"URL":"https:\/\/doi.org\/10.1126\/sciadv.aeb1134","relation":{},"ISSN":["2375-2548"],"issn-type":[{"value":"2375-2548","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,3]]},"assertion":[{"value":"2025-08-01","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-03-04","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-04-03","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"eaeb1134"}}