{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T23:25:35Z","timestamp":1787181935057,"version":"build-2736575974"},"reference-count":29,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,6,13]],"date-time":"2026-06-13T00:00:00Z","timestamp":1781308800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T00:00:00Z","timestamp":1787184000000},"content-version":"vor","delay-in-days":68,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"the Program of Taizhou School of Clinical Medicine of Nanjing Medical University","award":["No. TZKY20230106"],"award-info":[{"award-number":["No. TZKY20230106"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["BMC Med Genomics"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Aortic dissection (AD) is a life-threatening cardiovascular disease with limited effective therapeutic options. Phenotypic switching of aortic vascular smooth muscle cells (VSMCs) from a contractile to a pathological state is a critical driver of AD progression. However, the molecular regulators governing this transition remain incompletely understood. This study aimed to identify a critical regulator of VSMC phenotypic switching in AD and to investigate its underlying mechanisms and translational relevance.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Single-cell RNA sequencing (scRNA-seq) and bulk RNA sequencing datasets obtained from the Gene Expression Omnibus (GEO) database were integrated for analysis. To enhance robustness and reduce dataset-specific bias, weighted gene co-expression network analysis (WGCNA) was performed in both aortic aneurysm (AA) and AD cohorts to identify gene modules associated with VSMC function. Overlapping VSMC-related modules were intersected to define candidate genes. Key regulators were further prioritized in AD datasets using LASSO regression and validated by single-cell RNA sequencing (scRNA-seq) pseudotime trajectory analysis to delineate dynamic gene expression during VSMC phenotypic switching. Functional validation was conducted in an angiotensin II (Ang II)-induced experimental AD mouse model with AAV9-mediated CASQ2 overexpression, as well as in primary VSMCs isolated from the abdominal aorta of mice and treated with Ang II in vitro. Aortic morphology, medial calcification, VSMC phenotypic markers, intracellular Ca\n                      <jats:sup>2+<\/jats:sup>\n                      homeostasis, and endoplasmic reticulum (ER) stress signaling were systematically evaluated.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>WGCNA identified a conserved gene module comprising 64 genes associated with VSMC phenotypic transition. Integrative LASSO and scRNA-seq analyses prioritized CASQ2 as a key gene with reduced expression in AD VSMCs. Pseudotime analysis revealed progressive downregulation of CASQ2 during osteochondrogenic phenotypic switching. In AngII-induced experimental AD mice, CASQ2 expression was decreased in the aortic media and accompanied by enhanced medial calcification. In vivo, Ang II infusion markedly reduced aortic CASQ2 expression and induced medial dilation and calcification, accompanied by increased mortality. AAV9-mediated CASQ2 overexpression significantly improved survival, attenuated aneurysmal enlargement, reduced vascular calcification and partially restored contractile marker expression. In vitro, Ang II stimulation decreased CASQ2 levels in primary VSMCs, promoted osteochondrogenic marker expression, and induced intracellular Ca\u00b2\u207a overload. CASQ2 overexpression restored calcium-release complex components, suppressed cytosolic Ca\u00b2\u207a elevation, and markedly reduced ER stress activation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>CASQ2 may represent a VSMC-enriched functional regulator involved in AD-associated phenotypic switching through calcium homeostasis and ER stress. These findings suggest that CASQ2 represents a potential therapeutic target in AD. Further studies are needed to determine its disease specificity and translational relevance.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12920-026-02410-w","type":"journal-article","created":{"date-parts":[[2026,6,13]],"date-time":"2026-06-13T05:25:11Z","timestamp":1781328311000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Loss of CASQ2 promotes vascular smooth muscle cell phenotypic switching in aortic dissection uncovered by integrated single-cell transcriptomics"],"prefix":"10.1186","volume":"19","author":[{"given":"Kaiyan","family":"Chen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meixiang","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiyuan","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingquan","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Xia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maomao","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junchao","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,13]]},"reference":[{"issue":"9970","key":"2410_CR1","doi-asserted-by":"publisher","first-page":"800","DOI":"10.1016\/S0140-6736(14)61005-9","volume":"385","author":"CA Nienaber","year":"2015","unstructured":"Nienaber CA, Clough RE. 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