{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T03:02:10Z","timestamp":1760151730439,"version":"build-2065373602"},"reference-count":47,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2022,4,14]],"date-time":"2022-04-14T00:00:00Z","timestamp":1649894400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01-HL112248","R01-DK054254","R01-DK083850","R01DK124126","R15HL145573"],"award-info":[{"award-number":["R01-HL112248","R01-DK054254","R01-DK083850","R01DK124126","R15HL145573"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>(1) Background: Mice with global Ceacam1 deletion developed plaque-like aortic lesions even on C57BL\/6J background in the presence of increased endothelial cell permeability and insulin resistance. Loss of endothelial Ceacam1 gene caused endothelial dysfunction and reduced vascular integrity without affecting systemic insulin sensitivity. Because endothelial cell injury precedes atherosclerosis, we herein investigated whether the loss of endothelial Ceacam1 initiates atheroma formation in the absence of insulin resistance. (2) Methods: Endothelial cell-specific Ceacam1 null mice on C57BL\/6J.Ldlr\u2212\/\u2212 background (Ldlr\u2212\/\u2212VECadCre+Cc1fl\/fl) were fed an atherogenic diet for 3\u20135 months before metabolic, histopathological, and en-face analysis of aortae were compared to their control littermates. Sirius Red stain was also performed on liver sections to analyze hepatic fibrosis. (3) Results: These mice displayed insulin sensitivity without significant fat deposition on aortic walls despite hypercholesterolemia. They also displayed increased inflammation and fibrosis. Deleting Ceacam1 in endothelial cells caused hyperactivation of VEGFR2\/Shc\/NF-\u03baB pathway with resultant transcriptional induction of NF-\u03baB targets. These include IL-6 that activates STAT3 inflammatory pathways, in addition to endothelin-1 and PDGF-B profibrogenic effectors. It also induced the association between SHP2 phosphatase and VEGFR2, downregulating the Akt\/eNOS pathway and reducing nitric oxide production, a characteristic feature of endothelial dysfunction. Similarly, hepatic inflammation and fibrosis developed in Ldlr\u2212\/\u2212VECadCre+Cc1fl\/fl mice without an increase in hepatic steatosis. (4) Conclusions: Deleting endothelial cell Ceacam1 caused hepatic and aortic inflammation and fibrosis with increased endothelial dysfunction and oxidative stress in the presence of hypercholesterolemia. However, this did not progress into frank atheroma formation. Because these mice remained insulin sensitive, the study provides an in vivo demonstration that insulin resistance plays a critical role in the pathogenesis of frank atherosclerosis.<\/jats:p>","DOI":"10.3390\/ijms23084335","type":"journal-article","created":{"date-parts":[[2022,4,14]],"date-time":"2022-04-14T21:44:06Z","timestamp":1649972646000},"page":"4335","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Aortic Fibrosis in Insulin-Sensitive Mice with Endothelial Cell-Specific Deletion of Ceacam1 Gene"],"prefix":"10.3390","volume":"23","author":[{"given":"Raghd","family":"Abu Helal","sequence":"first","affiliation":[{"name":"Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH 45701, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Harrison T.","family":"Muturi","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH 45701, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Abraham D.","family":"Lee","sequence":"additional","affiliation":[{"name":"Center for Diabetes and Endocrine Research, College of Medicine, University of Toledo, Toledo, OH 43606, USA"},{"name":"School of Exercise and Rehabilitation Sciences, College of Health and Human Services, University of Toledo, Toledo, OH 43606, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7973-6242","authenticated-orcid":false,"given":"Wei","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Joan C. Edwards School of Medicine at Marshall University, Huntington, WV 25755, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7983-2090","authenticated-orcid":false,"given":"Hilda E.","family":"Ghadieh","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH 45701, USA"},{"name":"Center for Diabetes and Endocrine Research, College of Medicine, University of Toledo, Toledo, OH 43606, USA"},{"name":"Department of Biomedical Sciences, Faculty of Medicine and Medical Sciences, University of Balamand, El-Koura P.O. Box 100, Lebanon"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sonia M.","family":"Najjar","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH 45701, USA"},{"name":"Center for Diabetes and Endocrine Research, College of Medicine, University of Toledo, Toledo, OH 43606, USA"},{"name":"Diabetes Institute, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH 45701, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,4,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1038\/s41572-019-0106-z","article-title":"Atherosclerosis","volume":"5","author":"Libby","year":"2019","journal-title":"Nat. Rev. Dis. 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