{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T01:40:14Z","timestamp":1785548414188,"version":"3.56.0"},"reference-count":37,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2024,7,25]],"date-time":"2024-07-25T00:00:00Z","timestamp":1721865600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000780","name":"European Union\u2014Next Generation EU","doi-asserted-by":"publisher","award":["PNRR-MR1-2022-12376699"],"award-info":[{"award-number":["PNRR-MR1-2022-12376699"]}],"id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Thoracic aortic aneurysms (TAAs) represent a serious health concern, as they are associated with early aortic dissection and rupture. TAA formation is triggered by genetic conditions, in particular Marfan syndrome (MFS) and bicuspid aortic valve (BAV). During the aneurysmatic process, aortic endothelial cells can undergo endothelial-to-mesenchymal transition (End\u2013MT) with consequent phenotypic and functional alterations. We previously documented that MFS TAA is characterized by miR-632\u2013driven End\u2013MT exacerbation, whereas in BAV aortopathy, the occurrence of this process remains still controversial. We investigated the End\u2013MT process and the underlined regulatory mechanisms in BAV, TAV and MFS TAA tissues. Gene expression and immunohistochemical analysis were performed in order to analyze some important miRNAs and genes characterizing End\u2013MT. We documented that BAV endothelium maintains the expression of the endothelial homeostasis markers, such as ERG, CD31 and miR-126-5p, while it shows lower levels of miR-632 and mesenchymal markers compared with MFS. Interestingly, we also found higher levels of miR-632 in MFS patients\u2019 blood. Our findings definitively demonstrate that the End\u2013MT process does not characterize BAV that, among the other TAAs, better maintains the endothelial features. In addition, our results suggest miR-632 as a promising diagnostic\/prognostic factor in MFS aortopathy.<\/jats:p>","DOI":"10.3390\/cells13151252","type":"journal-article","created":{"date-parts":[[2024,7,25]],"date-time":"2024-07-25T13:10:28Z","timestamp":1721913028000},"page":"1252","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["miRNA-Driven Regulation of Endothelial-to-Mesenchymal Transition Differs among Thoracic Aortic Aneurysms"],"prefix":"10.3390","volume":"13","author":[{"given":"Sonia","family":"Terriaca","sequence":"first","affiliation":[{"name":"Anatomic Pathology, Fondazione Policlinico Tor Vergata, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8458-4108","authenticated-orcid":false,"given":"Maria Giovanna","family":"Scioli","sequence":"additional","affiliation":[{"name":"Anatomic Pathology, Department of Biomedicine and Prevention, Tor Vergata University, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabio","family":"Bertoldo","sequence":"additional","affiliation":[{"name":"Cardiac Surgery Unit, Department of Surgery, Tor Vergata University, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6488-1965","authenticated-orcid":false,"given":"Calogera","family":"Pisano","sequence":"additional","affiliation":[{"name":"Cardiac Surgery Unit, Department of Surgery, Tor Vergata University, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4005-3110","authenticated-orcid":false,"given":"Paolo","family":"Nardi","sequence":"additional","affiliation":[{"name":"Cardiac Surgery Unit, Department of Surgery, Tor Vergata University, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5393-1007","authenticated-orcid":false,"given":"Carmela Rita","family":"Balistreri","sequence":"additional","affiliation":[{"name":"Cellular and Molecular Laboratory, Department of Biomedicine, Neuroscience and Advanced Diagnostics (Bi.N.D.), University of Palermo, 90134 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniele","family":"Magro","sequence":"additional","affiliation":[{"name":"Cellular and Molecular Laboratory, Department of Biomedicine, Neuroscience and Advanced Diagnostics (Bi.N.D.), University of Palermo, 90134 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9668-0925","authenticated-orcid":false,"given":"Beatrice","family":"Belmonte","sequence":"additional","affiliation":[{"name":"Tumor Immunology Unit, Department of Health Sciences, University of Palermo, 90134 Palermo, Italy"},{"name":"Azienda sanitaria Provinciale di Catania (ASP), 95124 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9068-2225","authenticated-orcid":false,"given":"Luca","family":"Savino","sequence":"additional","affiliation":[{"name":"Anatomic Pathology, Fondazione Policlinico Tor Vergata, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amedeo","family":"Ferlosio","sequence":"additional","affiliation":[{"name":"Anatomic Pathology, Department of Biomedicine and Prevention, Tor Vergata University, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7202-5854","authenticated-orcid":false,"given":"Augusto","family":"Orlandi","sequence":"additional","affiliation":[{"name":"Anatomic Pathology, Department of Biomedicine and Prevention, Tor Vergata University, 00133 Rome, Italy"},{"name":"Department of Biomedical Sciences, Catholic University Our Lady of Good Counsel, 1001 Tirana, Albania"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,7,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/j.hjc.2022.09.009","article-title":"The genetic basis of thoracic aortic disease: The future of aneurysm classification?","volume":"69","author":"Salmasi","year":"2023","journal-title":"Hell. J. Cardiol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1146\/annurev.med.51.1.481","article-title":"The Marfan syndrome","volume":"51","author":"Pyeritz","year":"2000","journal-title":"Annu. Rev. Med."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Dawson, A., Li, Y., Li, Y., Ren, P., Vasquez, H.G., Zhang, C., Rebello, K.R., Ageedi, W., Azares, A.R., and Mattar, A.B. (2021). Single-Cell Analysis of Aneurysmal Aortic Tissue in Patients with Marfan Syndrome Reveals Dysfunctional TGF-\u03b2 Signaling. Genes, 13.","DOI":"10.3390\/genes13010095"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Yassine, N.M., Shahram, J.T., and Body, S.C. (2017). Pathogenic Mechanisms of Bicuspid Aortic Valve Aortopathy. Front. Physiol., 8.","DOI":"10.3389\/fphys.2017.00687"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Gillis, E., Kumar, A.A., Luyckx, I., Preuss, C., Cannaerts, E., van de Beek, G., Wieschendorf, B., Alaerts, M., Bolar, N., and Vandeweyer, G. (2017). Candidate Gene Resequencing in a Large Bicuspid Aortic Valve-Associated Thoracic Aortic Aneurysm Cohort: SMAD6 as an Important Contributor. Front. Physiol., 8.","DOI":"10.3389\/fphys.2017.00400"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Ma, M., Li, Z., Mohamed, M.A., Liu, L., and Wei, X. (2021). Aortic root aortopathy in bicuspid aortic valve associated with high genetic risk. BMC Cardiovasc. Disord., 21.","DOI":"10.1186\/s12872-021-02215-y"},{"key":"ref_7","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_8","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1093\/cvr\/cvx253","article-title":"Endothelial-mesenchymal transition in atherosclerosis","volume":"114","author":"Souilhol","year":"2018","journal-title":"Cardiovasc. Res."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Terriaca, S., Scioli, M.G., Pisano, C., Ruvolo, G., Ferlosio, A., and Orlandi, A. (2023). miR-632 Induces DNAJB6 Inhibition Stimulating Endothelial-to-Mesenchymal Transition and Fibrosis in Marfan Syndrome Aortopathy. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms242015133"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1161\/01.RES.77.1.1","article-title":"Molecular regulation of atrioventricular valvuloseptal morphogenesis","volume":"77","author":"Eisenberg","year":"1995","journal-title":"Circ. Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1795","DOI":"10.1161\/CIRCULATIONAHA.111.040352","article-title":"Epithelial-to-mesenchymal and endothelial-to-mesenchymal transition: From cardiovascular development to disease","volume":"125","author":"Kovacic","year":"2012","journal-title":"Circulation"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"492","DOI":"10.1002\/dvdy.24589","article-title":"Endothelial-to-mesenchymal transition in cardiovascular diseases: Developmental signaling pathways gone awry","volume":"247","year":"2018","journal-title":"Dev. Dyn."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1089\/ten.teb.2015.0167","article-title":"Environmental Influences on Endothelial to Mesenchymal Transition in Developing Implanted Cardiovascular Tissue-Engineered Grafts","volume":"22","author":"Muylaert","year":"2016","journal-title":"Tissue Eng. Part B Rev."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1007\/s13239-018-0363-0","article-title":"The Roles of Matrix Stiffness and \u00df-Catenin Signaling in Endothelial-to-Mesenchymal Transition of Aortic Valve Endothelial Cells","volume":"9","author":"Zhong","year":"2018","journal-title":"Cardiovasc. Eng. Technol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1186\/s12967-018-1429-3","article-title":"Deregulated microRNA and mRNA expression profiles in the peripheral blood of patients with Marfan syndrome","volume":"16","author":"Kahraman","year":"2018","journal-title":"J. Transl. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"406","DOI":"10.5483\/BMBRep.2018.51.8.105","article-title":"Exosomes derived from microRNA-584 transfected mesenchymal stem cells: Novel alternative therapeutic vehicles for cancer therapy","volume":"51","author":"Kim","year":"2018","journal-title":"BMB Rep."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1016\/j.cellsig.2011.08.012","article-title":"Regulation of TGF\u03b2 receptor trafficking and signaling by atypical protein kinase C","volume":"24","author":"Gunaratne","year":"2012","journal-title":"Cell. Signal."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"21364","DOI":"10.1038\/s41598-020-78206-4","article-title":"Canonical and noncanonical TGF-\u03b2 signaling regulate fibrous tissue differentiation in the axial skeleton","volume":"10","author":"Clayton","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1016\/j.devcel.2008.07.002","article-title":"The endothelial-specific microRNA miR-126 governs vascular integrity and angiogenesis","volume":"15","author":"Wang","year":"2008","journal-title":"Dev. Cell"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Pisano, C., Terriaca, S., Scioli, M.G., Nardi, P., Altieri, C., Orlandi, A., Ruvolo, G., and Balistreri, C.R. (2022). The Endothelial Transcription Factor ERG Mediates a Differential Role in the Aneurysmatic Ascending Aorta with Bicuspid or Tricuspid Aorta Valve: A Preliminary Study. Int. J. Mol. Sci., 23.","DOI":"10.20944\/preprints202208.0030.v1"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1990","DOI":"10.1161\/ATVBAHA.110.211706","article-title":"Ets-1 and Ets-2 regulate the expression of microRNA-126 in endothelial cells","volume":"30","author":"Harris","year":"2010","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"7078","DOI":"10.1111\/jcmm.16727","article-title":"Epigenetic down-regulation of microRNA-126 in scleroderma endothelial cells is associated with impaired responses to VEGF and defective angiogenesis","volume":"25","author":"Wang","year":"2021","journal-title":"J. Cell. Mol. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"7600","DOI":"10.1111\/jcmm.15396","article-title":"miR-126 reduces trastuzumab resistance by targeting PIK3R2 and regulating AKT\/mTOR pathway in breast cancer cells","volume":"24","author":"Fu","year":"2020","journal-title":"J. Cell. Mol. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1111\/crj.13646","article-title":"miR-126-5p expression in the plasma of patients with sepsis-induced acute lung injury and its correlation with inflammation and immune function","volume":"17","author":"Mao","year":"2023","journal-title":"Clin. Respir. J."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1016\/j.bbadis.2016.02.006","article-title":"Notch-dependent EMT is attenuated in patients with aortic aneurysm and bicuspid aortic valve","volume":"1862","author":"Kostina","year":"2016","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1101\/gad.276304","article-title":"Notch promotes epithelial-mesenchymal transition during cardiac development and oncogenic transformation","volume":"18","author":"Timmerman","year":"2004","journal-title":"Genes Dev."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1038\/s41588-018-0265-y","article-title":"ROBO4 variants predispose individuals to bicuspid aortic valve and thoracic aortic aneurysm","volume":"51","author":"Gould","year":"2019","journal-title":"Nat. Genet."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"35712","DOI":"10.1038\/srep35712","article-title":"Mesenchymal state of intimal cells may explain higher propensity to ascending aortic aneurysm in bicuspid aortic valves","volume":"6","author":"Maleki","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1136\/jmg.2009.072785","article-title":"The revised Ghent nosology for the Marfan syndrome","volume":"47","author":"Loeys","year":"2010","journal-title":"J. Med. Genet."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1093\/ejechocard\/jeq056","article-title":"Echocardiography in aortic diseases: EAE recommendations for clinical practice","volume":"11","author":"Evangelista","year":"2010","journal-title":"Eur. J. Echocardiogr."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1097\/00000658-199109000-00013","article-title":"Sixteen-year experience with aortic root replacement. Results of 172 operations","volume":"214","author":"Kouchoukos","year":"1991","journal-title":"Ann. Surg."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1016\/j.yexcr.2005.10.008","article-title":"Phenotypic heterogeneity influences the behavior of rat aortic smooth muscle cells in collagen lattice","volume":"311","author":"Orlandi","year":"2005","journal-title":"Exp. Cell Res."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"D\u2019Amico, F., Doldo, E., Pisano, C., Scioli, M.G., Centofanti, F., Proietti, G., Falconi, M., Sangiuolo, F., Ferlosio, A., and Ruvolo, G. (2020). Specific miRNA and Gene Deregulation Characterize the Increased Angiogenic Remodeling of Thoracic Aneurysmatic Aortopathy in Marfan Syndrome. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21186886"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"101709","DOI":"10.1101\/pdb.top101709","article-title":"Quantifying and Storing RNA","volume":"2020","author":"Green","year":"2020","journal-title":"Cold Spring Harb. Protoc."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method","volume":"25","author":"Livak","year":"2001","journal-title":"Methods"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"20869","DOI":"10.1038\/s41598-023-47971-3","article-title":"Optimized RT-qPCR and a novel normalization method for validating circulating miRNA biomarkers in ageing-related diseases","volume":"13","author":"Want","year":"2023","journal-title":"Sci. Rep."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"4170","DOI":"10.1038\/s41467-022-31890-4","article-title":"Dysfunctional ERG signaling drives pulmonary vascular aging and persistent fibrosis","volume":"13","author":"Caporarello","year":"2022","journal-title":"Nat. Commun."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/13\/15\/1252\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T15:23:23Z","timestamp":1760109803000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/13\/15\/1252"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,7,25]]},"references-count":37,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2024,8]]}},"alternative-id":["cells13151252"],"URL":"https:\/\/doi.org\/10.3390\/cells13151252","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,7,25]]}}}