{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T17:03:38Z","timestamp":1784653418504,"version":"3.55.0"},"reference-count":38,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T00:00:00Z","timestamp":1784505600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background: Thoracic aortic aneurysm (TAA) is a potentially life-threatening degenerative disease whose principal danger arises from progressive aortic dilation with the attendant risk of rupture and dissection and which is characterized by extracellular matrix breakdown, smooth muscle loss, and endothelial dysfunction. Caveolae, plasma membrane microdomains built from caveolins (CAV1-3) and cavins (CAVIN1-4), govern nitric oxide (NO) signaling, endocytosis, and mechanotransduction. We hypothesized that downregulation of caveolae-associated genes, driven in part by microRNAs, contributes to endothelial failure and vascular remodeling in TAA. Methods: Normalized transcriptomic expression values for five caveolae-associated genes were retrieved from the GSE26155 dataset (43 TAA and 43 control aortas) using GEO2R. Differential expression was assessed for CAV1, CAV2, CAV3, CAVIN1, and CAVIN2, and Spearman correlation with Deming regression explored inter-gene relationships. Functional enrichment (Enrichr) and experimentally validated microRNA-target interactions (miRTarBase) were used to infer regulatory and mechanistic networks. CpG island mapping and gene-gene interactome construction (GeneMANIA) complemented the analyses. Results: CAV1 and CAV2 were downregulated in TAA at nominal significance (CAV1, p = 0.0225; CAV2, p = 0.0361); after Benjamini\u2013Hochberg correction across the five candidate genes both differences attenuated to a consistent trend (q approximately 0.09), while the two caveolins were strongly co-expressed (Spearman r = 0.527, p &lt; 0.001; Deming CAV2 = 1.881 \u00d7 CAV1-0.892), indicating coordinated transcriptional regulation. Network analysis linked both genes to NOS3, NOSTRIN, EGFR, HRAS, and RAC1, consistent with impaired endothelial nitric oxide and GTPase signaling. Gene Ontology enrichment highlighted endothelial proliferation, nitric oxide metabolism, calcium homeostasis, vesicle organization, and MAPK regulation. Database-supported analysis (miRTarBase) identified miR-93-5p, miR-199a-3p, miR-203a-3p, and the miR-29 family as experimentally validated candidate repressors of CAV1\/CAV2. Conclusions: This integrative transcriptomic and microRNA analysis identifies coordinated CAV1 and CAV2 downregulation as a candidate molecular event in thoracic aortic aneurysm, associated with caveolar loss, endothelial dysfunction, and disrupted nitric oxide homeostasis. The CAV1\/CAV2-microRNA axis represents a candidate mechanistic signature warranting further investigation as a potential therapeutic target in aortic disease.<\/jats:p>","DOI":"10.3390\/genes17070827","type":"journal-article","created":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T16:16:39Z","timestamp":1784650599000},"page":"827","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Coordinated Transcriptional Repression of CAV1 and CAV2 in Thoracic Aortic Aneurysm: A microRNA Regulatory Network Analysis"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5417-6392","authenticated-orcid":false,"given":"Dimitrios E.","family":"Magouliotis","sequence":"first","affiliation":[{"name":"Department of Cardiac Surgery Research, Lankenau Institute for Medical Research, Wynnewood, PA 19096, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1822-768X","authenticated-orcid":false,"given":"Serge","family":"Sicouri","sequence":"additional","affiliation":[{"name":"Department of Cardiac Surgery Research, Lankenau Institute for Medical Research, Wynnewood, PA 19096, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vasiliki","family":"Androutsopoulou","sequence":"additional","affiliation":[{"name":"Department of Cardiothoracic Surgery, Faculty of Medicine, University of Thessaly, 41110 Larissa, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3754-6704","authenticated-orcid":false,"given":"Massimo","family":"Baudo","sequence":"additional","affiliation":[{"name":"Department of Cardiac Surgery Research, Lankenau Institute for Medical Research, Wynnewood, PA 19096, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thanos","family":"Athanasiou","sequence":"additional","affiliation":[{"name":"Department of Surgery and Cancer, Imperial College London, London W12 0NN, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2409-2184","authenticated-orcid":false,"given":"Dimitrios V.","family":"Avgerinos","sequence":"additional","affiliation":[{"name":"Department of Cardiac Surgery, Onassis Cardiac Surgery Center, 17674 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7159-2478","authenticated-orcid":false,"given":"John","family":"Skoularigis","sequence":"additional","affiliation":[{"name":"Department of Cardiology, University Hospital of Larissa, Biopolis, 41110 Larissa, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7406-5427","authenticated-orcid":false,"given":"Grigorios","family":"Giamouzis","sequence":"additional","affiliation":[{"name":"Department of Cardiology, University Hospital of Larissa, Biopolis, 41110 Larissa, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0471-0910","authenticated-orcid":false,"given":"Basel","family":"Ramlawi","sequence":"additional","affiliation":[{"name":"Department of Cardiac Surgery Research, Lankenau Institute for Medical Research, Wynnewood, PA 19096, USA"},{"name":"Department of Cardiac Surgery, Lankenau Heart Institute, Main Line Health, Wynnewood, PA 19096, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Xanthopoulos","sequence":"additional","affiliation":[{"name":"Department of Cardiology, University Hospital of Larissa, Biopolis, 41110 Larissa, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1016\/j.athoracsur.2024.01.021","article-title":"EACTS\/STS Guidelines for Diagnosing and Treating Acute and Chronic Syndromes of the Aortic Organ","volume":"118","author":"Czerny","year":"2024","journal-title":"Ann. Thorac. Surg."},{"key":"ref_2","first-page":"3107879","article-title":"Phenotypic and Functional Changes of Endothelial and Smooth Muscle Cells in Thoracic Aortic Aneurysms","volume":"2016","author":"Malashicheva","year":"2016","journal-title":"Int. J. Vasc. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1038\/nature10145","article-title":"Lessons on the pathogenesis of aneurysm from heritable conditions","volume":"473","author":"Lindsay","year":"2011","journal-title":"Nature"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Magouliotis, D.E., Arjomandi Rad, A., Kourliouros, A., Viviano, A., Koulouroudias, M., Salmasi, M.Y., Briasoulis, A., Triposkiadis, F., Skoularigis, J., and Athanasiou, T. (2023). Transcriptomic Analysis of Tight Junction Proteins Demonstrates the Aberrant Expression and Function of Zona Occludens 2 (ZO-2) Protein in Stanford Type A Aortic Dissection. J. Pers. Med., 13.","DOI":"10.3390\/jpm13121697"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2285","DOI":"10.1161\/ATVBAHA.123.319329","article-title":"Single-Molecule Spatial Transcriptomics of Human Thoracic Aortic Aneurysms Uncovers Calcification-Related CARTPT-Expressing Smooth Muscle Cells","volume":"43","author":"Mizrak","year":"2023","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"eadg6298","DOI":"10.1126\/scitranslmed.adg6298","article-title":"Bioengineered vascular grafts with a pathogenic TGFBR1 variant model aneurysm formation in vivo and reveal underlying collagen defects","volume":"16","author":"Yang","year":"2024","journal-title":"Sci. Transl. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1152\/physrev.00041.2003","article-title":"Molecular regulation of vascular SMC differentiation","volume":"84","author":"Owens","year":"2004","journal-title":"Physiol. Rev."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Magouliotis, D.E., Sicouri, S., Rad, A.A., Skoularigis, J., Giamouzis, G., Xanthopoulos, A., Karamolegkou, A.P., Viviano, A., Athanasiou, T., and Ramlawi, B. (2025). In-depth computational analysis reveals the significant dysregulation of key gap junction proteins (GJPs) driving thoracic aortic aneurysm development. Hell. J. Cardiol., in press.","DOI":"10.1016\/j.hjc.2025.01.001"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1093\/ejcts\/ezab338","article-title":"In-depth bioinformatic study of the cadherin 5 interactome in patients with thoracic aortic aneurysm unveils 8 novel biomarkers","volume":"61","author":"Magouliotis","year":"2021","journal-title":"Eur. J. Cardio-Thorac. Surg."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Magouliotis, D.E., Sicouri, S., Sicouri, N., Baudo, M., Cabrucci, F., Yamashita, Y., and Ramlawi, B. (2025). Epigenetic Biomarkers in Thoracic Aortic Aneurysm, Dissection, and Bicuspid Aortopathy: A Comprehensive Review. Biomolecules, 15.","DOI":"10.3390\/biom15040568"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Curry-Koski, T., Gusek, B., Potter, R.M., Jones, T.B., Dickman, R., Johnson, N., Stallone, J.N., Rahimian, R., Vallejo-Elias, J., and Esfandiarei, M. (2024). Genetic Manipulation of Caveolin-1 in a Transgenic Mouse Model of Aortic Root Aneurysm: Sex-Dependent Effects on Endothelial and Smooth Muscle Function. Int. J. Mol. Sci., 25.","DOI":"10.1101\/2024.07.29.605631"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Little, J., Higgins, J.P., Ioannidis, J.P., Moher, D., Gagnon, F., von Elm, E., Khoury, M.J., Cohen, B., Davey-Smith, G., and Grimshaw, J. (2009). STrengthening the REporting of Genetic Association Studies (STREGA): An extension of the STROBE statement. PLoS Med., 6.","DOI":"10.1371\/journal.pmed.1000022"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1365","DOI":"10.2119\/molmed.2011.00286","article-title":"Unraveling divergent gene expression profiles in bicuspid and tricuspid aortic valve patients with thoracic aortic dilatation: The ASAP study","volume":"17","author":"Folkersen","year":"2011","journal-title":"Mol. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"965","DOI":"10.1002\/(SICI)1097-0258(19970515)16:9<965::AID-SIM509>3.0.CO;2-O","article-title":"A comparison of goodness-of-fit tests for the logistic regression model","volume":"16","author":"Hosmer","year":"1997","journal-title":"Stat. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"W214","DOI":"10.1093\/nar\/gkq537","article-title":"The GeneMANIA prediction server: Biological network integration for gene prioritization and predicting gene function","volume":"38","author":"Donaldson","year":"2010","journal-title":"Nucleic Acids Res."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Chen, E.Y., Tan, C.M., Kou, Y., Duan, Q., Wang, Z., Meirelles, G.V., Clark, N.R., and Ma\u2019ayan, A. (2013). Enrichr: Interactive and collaborative HTML5 gene list enrichment analysis tool. BMC Bioinform., 14.","DOI":"10.1186\/1471-2105-14-128"},{"key":"ref_17","unstructured":"(2025, March 20). miRTarBase. Curated Experimentally Validated miRNA-Target Interactions. Version 2023. Available online: https:\/\/mirtarbase.cuhk.edu.cn."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1016\/S0168-9525(00)02024-2","article-title":"EMBOSS: The European Molecular Biology Open Software Suite","volume":"16","author":"Rice","year":"2000","journal-title":"Trends Genet."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1038\/nrm3512","article-title":"Caveolae as plasma-membrane sensors, protectors and organizers","volume":"14","author":"Parton","year":"2013","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"761","DOI":"10.1073\/pnas.0407224102","article-title":"Dissecting the molecular control of endothelial NO synthase by caveolin-1 using cell-permeable peptides","volume":"102","author":"Bernatchez","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"38121","DOI":"10.1074\/jbc.M105408200","article-title":"Caveolin-1 null mice are viable but show evidence of hyperproliferative and vascular abnormalities","volume":"276","author":"Razani","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2449","DOI":"10.1126\/science.1062688","article-title":"Loss of caveolae, vascular dysfunction, and pulmonary defects in caveolin-1 gene-disrupted mice","volume":"293","author":"Drab","year":"2001","journal-title":"Science"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"17822","DOI":"10.1038\/s41598-022-20713-7","article-title":"Caveolin-1 is a primary determinant of endothelial stiffening associated with dyslipidemia, disturbed flow, and ageing","volume":"12","author":"Paul","year":"2022","journal-title":"Sci. Rep."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/S1937-6448(10)82003-9","article-title":"Lipid rafts, caveolae and their endocytosis","volume":"282","author":"Lajoie","year":"2010","journal-title":"Int. Rev. Cell Mol. Biol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1002\/jcp.10344","article-title":"Mechanosensing role of caveolae and caveolar constituents in human endothelial cells","volume":"197","author":"Spisni","year":"2003","journal-title":"J. Cell. Physiol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1221","DOI":"10.1172\/JCI21968","article-title":"Oxidant stress from nitric oxide synthase-3 uncoupling stimulates cardiac pathologic remodeling from chronic pressure load","volume":"115","author":"Takimoto","year":"2005","journal-title":"J. Clin. Investig."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1097\/MOH.0000000000000424","article-title":"MicroRNAs in endothelial cell homeostasis and vascular disease","volume":"25","author":"Suarez","year":"2018","journal-title":"Curr. Opin. Hematol."},{"key":"ref_28","first-page":"124","article-title":"Roles of microRNAs in abdominal aortic aneurysm pathogenesis and the possibility of their use as biomarkers","volume":"16","author":"Borek","year":"2019","journal-title":"Kardiochir. Torakochirurgia Pol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1016\/j.cell.2018.03.006","article-title":"Metazoan microRNAs","volume":"173","author":"Bartel","year":"2018","journal-title":"Cell"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1230","DOI":"10.1089\/ars.2014.6158","article-title":"Central role of eNOS in the maintenance of endothelial homeostasis","volume":"22","author":"Heiss","year":"2015","journal-title":"Antioxid. Redox Signal."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/j.ceb.2020.10.008","article-title":"Caveolae: Mechanosensing and mechanotransduction devices linking membrane trafficking to mechanoadaptation","volume":"68","author":"Lolo","year":"2021","journal-title":"Curr. Opin. Cell Biol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"H677","DOI":"10.1152\/ajpheart.01092.2005","article-title":"Caveolin-1 and regulation of cellular cholesterol homeostasis","volume":"291","author":"Frank","year":"2006","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"796","DOI":"10.1111\/j.1582-4934.2008.00295.x","article-title":"Caveolae structure and function","volume":"12","author":"Thomas","year":"2008","journal-title":"J. Cell. Mol. Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1130","DOI":"10.1111\/j.1582-4934.2008.00331.x","article-title":"Caveolin-1: An ambiguous partner in cell signalling and cancer","volume":"12","author":"Quest","year":"2008","journal-title":"J. Cell. Mol. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1449","DOI":"10.1089\/ars.2010.3647","article-title":"Go with the flow: How Kruppel-like factor 2 regulates the vasoprotective effects of shear stress","volume":"15","author":"Nayak","year":"2011","journal-title":"Antioxid. Redox Signal."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"3391","DOI":"10.1167\/iovs.10-6165","article-title":"Coordinated regulation of extracellular matrix synthesis by the microRNA-29 family in the trabecular meshwork","volume":"52","author":"Villarreal","year":"2011","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Sluiter, T.J., van Buul, J.D., Huveneers, S., Quax, P.H.A., and de Vries, M.R. (2021). Endothelial Barrier Function and Leukocyte Transmigration in Atherosclerosis. Biomedicines, 9.","DOI":"10.3390\/biomedicines9040328"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"H572","DOI":"10.1152\/ajpheart.00139.2025","article-title":"Role of membrane microdomains in cardiac protection: Strategies for diabetic cardiomyopathy","volume":"329","author":"Bonds","year":"2025","journal-title":"Am. J. Physiol. Heart Circ. Physiol."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/17\/7\/827\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T16:21:42Z","timestamp":1784650902000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/17\/7\/827"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,20]]},"references-count":38,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["genes17070827"],"URL":"https:\/\/doi.org\/10.3390\/genes17070827","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,20]]}}}