{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T06:23:49Z","timestamp":1790231029607,"version":"4.1.0"},"reference-count":11,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"6","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["ATVB"],"published-print":{"date-parts":[[2023,6]]},"abstract":"\n Background:<\/jats:title>\n \n Smooth muscle cell (SMC) phenotypic reprogramming toward a mixed synthetic-proteolytic state is a central feature of aortic root aneurysm in Marfan syndrome (MFS). Previous work identified\n Klf4<\/jats:italic>\n as a potential mediator of SMC plasticity in MFS.\n <\/jats:p>\n <\/jats:sec>\n \n Methods:<\/jats:title>\n \n MFS (\n Fbn1<\/jats:italic>\n \n C1041G\/+<\/jats:italic>\n <\/jats:sup>\n ) mouse strains with an inducible vascular SMC fluorescent reporter (\n MFS<\/jats:italic>\n \n SMC<\/jats:italic>\n <\/jats:sup>\n ) with or without SMC-specific deletion of\n Klf4<\/jats:italic>\n exons 2 to 3 (\n MFS<\/jats:italic>\n \n SMC-Klf4\u0394<\/jats:italic>\n <\/jats:sup>\n ) were generated. Simultaneous SMC tracing and\n Klf4<\/jats:italic>\n loss-of-function (\n Klf4\u0394<\/jats:italic>\n mice) was induced at 6 weeks of age. Aneurysm growth was assessed via serial echocardiography (4\u201324 weeks). Twenty-four-week-old mice were assessed via histology, RNA in situ hybridization, and aortic single-cell RNA sequencing.\n <\/jats:p>\n <\/jats:sec>\n \n Results:<\/jats:title>\n \n MFS mice demonstrated progressive aortic root dilatation compared with control (WT\n SMC<\/jats:sup>\n ) mice regardless of\n Klf4<\/jats:italic>\n genotype (\n P<\/jats:italic>\n <0.001), but there was no difference in aneurysm growth in\n MFS<\/jats:italic>\n \n SMC-Klf4\u0394<\/jats:italic>\n <\/jats:sup>\n versus\n MFS<\/jats:italic>\n \n SMC<\/jats:italic>\n <\/jats:sup>\n (\n P<\/jats:italic>\n =0.884). Efficient SMC\n Klf4<\/jats:italic>\n deletion was confirmed via lineage-stratified genotyping, RNA in situ hybridization, and immunohistochemistry. Single-cell RNA sequencing of traced SMCs revealed a highly similar pattern of phenotype modulation marked by loss of contractile markers (eg,\n Myh11, Cnn1<\/jats:italic>\n ) and heightened expression of matrix genes (eg,\n Col1a1, Fn1<\/jats:italic>\n ) between\n Klf4<\/jats:italic>\n genotypes. Pseudotemporal quantitation of SMC dedifferentiation confirmed that\n Klf4<\/jats:italic>\n deletion did not alter the global extent of phenotype modulation, but reduced expression of 23 genes during this phenotype transition in\n MFS<\/jats:italic>\n \n SMC-Klf4\u0394<\/jats:italic>\n <\/jats:sup>\n mice, including multiple chondrogenic genes expressed by only the most severely dedifferentiated SMCs (eg,\n Cytl1, Tnfrsf11b<\/jats:italic>\n ).\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions:<\/jats:title>\n \n Klf4<\/jats:italic>\n is not required to initiate SMC phenotype modulation in MFS aneurysm but may exert regulatory control over chondrogenic genes expressed in highly dedifferentiated SMCs.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1161\/atvbaha.122.318509","type":"journal-article","created":{"date-parts":[[2023,4,27]],"date-time":"2023-04-27T09:02:00Z","timestamp":1682586120000},"page":"971-978","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":8,"title":["Smooth Muscle Cell Klf4 Expression Is Not Required for Phenotype Modulation or Aneurysm Formation in Marfan Syndrome Mice\u2014Brief Report"],"prefix":"10.1161","volume":"43","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5291-5980","authenticated-orcid":true,"given":"Albert J.","family":"Pedroza","sequence":"first","affiliation":[{"name":"Department of Cardiothoracic Surgery, Stanford University School of Medicine, CA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9993-3817","authenticated-orcid":true,"given":"Alex R.","family":"Dalal","sequence":"additional","affiliation":[{"name":"Department of Cardiothoracic Surgery, Stanford University School of Medicine, CA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0453-9041","authenticated-orcid":true,"given":"Rohan","family":"Shad","sequence":"additional","affiliation":[{"name":"Department of Cardiothoracic Surgery, Stanford University School of Medicine, CA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nobu","family":"Yokoyama","sequence":"additional","affiliation":[{"name":"Department of Cardiothoracic Surgery, Stanford University School of Medicine, CA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1293-7784","authenticated-orcid":true,"given":"Ken","family":"Nakamura","sequence":"additional","affiliation":[{"name":"Department of Cardiothoracic Surgery, Stanford University School of Medicine, CA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olivia","family":"Mitchel","sequence":"additional","affiliation":[{"name":"Department of Cardiothoracic Surgery, Stanford University School of Medicine, CA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Casey","family":"Gilles","sequence":"additional","affiliation":[{"name":"Department of Cardiothoracic Surgery, Stanford University School of Medicine, CA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3548-2578","authenticated-orcid":true,"given":"William","family":"Hiesinger","sequence":"additional","affiliation":[{"name":"Department of Cardiothoracic Surgery, Stanford University School of Medicine, CA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0638-2025","authenticated-orcid":true,"given":"Michael P.","family":"Fischbein","sequence":"additional","affiliation":[{"name":"Department of Cardiothoracic Surgery, Stanford University School of Medicine, CA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.res.88.1.37"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.114.304412"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.120.314670"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.121.316600"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.120.046672"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2020.02.013"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm1666"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/nn.2467"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1242\/dev.129.11.2619"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.122.317381"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.120.315164"}],"container-title":["Arteriosclerosis, 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