{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T22:02:13Z","timestamp":1791237733572,"version":"4.1.0"},"reference-count":36,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2018,9,14]],"date-time":"2018-09-14T00:00:00Z","timestamp":1536883200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2018,9,14]],"date-time":"2018-09-14T00:00:00Z","timestamp":1536883200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Bicuspid aortic valve (BAV) is frequently associated with the development of ascending aortic aneurysm, even if the underlying mechanisms remain to be clarified. Here, we investigated if a deregulation of Notch1 signaling pathway and endothelial progenitor cells (EPCs) number is associated with BAV disease and an early ascending aortic aneurysm (AAA) onset. For this purpose, 70 subjects with BAV (M\/F 50\/20; mean age: 58.8\u2009\u00b1\u200914.8 years) and 70 subjects with tricuspid aortic valve (TAV) (M\/F 35\/35; mean age: 69.1\u2009\u00b1\u200912.8 years) and AAA complicated or not, were included. Interestingly, patients with AAA showed a significant increase in circulating Notch1 levels and EPC number than subjects without AAA. However, circulating Notch1 levels and EPC number were significantly lower in BAV subjects than TAV patients either in the presence or absence of AAA. Finally, Notch pathway was activated to a greater extent in aortic aneurysmatic portions with respect to healthy aortic fragments in both BAV and TAV patients. However, the expression of genes encoding components and ligands of Notch pathway in aortic tissues was significantly lower in BAV than TAV subjects. Our study demonstrates that BAV subjects are characterized by a significant decrease in both tissue and circulating levels of Notch pathway, and in blood EPC number than TAV patients, either in presence or absence of AAA disease.<\/jats:p>","DOI":"10.1038\/s41598-018-32170-2","type":"journal-article","created":{"date-parts":[[2018,9,10]],"date-time":"2018-09-10T11:03:42Z","timestamp":1536577422000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":52,"title":["Deregulation of Notch1 pathway and circulating endothelial progenitor cell (EPC) number in patients with bicuspid aortic valve with and without ascending aorta aneurysm"],"prefix":"10.1038","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5393-1007","authenticated-orcid":false,"given":"Carmela R.","family":"Balistreri","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Floriana","family":"Crapanzano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7903-7660","authenticated-orcid":false,"given":"Leonardo","family":"Schirone","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alberto","family":"Allegra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Calogera","family":"Pisano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanni","family":"Ruvolo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maurizio","family":"Forte","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ernesto","family":"Greco","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0221-6000","authenticated-orcid":false,"given":"Elena","family":"Cavarretta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonino G. M.","family":"Marullo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastiano","family":"Sciarretta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giacomo","family":"Frati","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2018,9,14]]},"reference":[{"key":"32170_CR1","doi-asserted-by":"publisher","first-page":"2789","DOI":"10.1016\/j.jacc.2009.12.068","volume":"55","author":"SC Siu","year":"2010","unstructured":"Siu, S. C. & Silversides, C. K. Bicuspid aortic valve disease. Journal of the American College of Cardiology 55, 2789\u20132800 (2010).","journal-title":"Journal of the American College of Cardiology"},{"key":"32170_CR2","doi-asserted-by":"publisher","first-page":"342984","DOI":"10.1155\/2015\/342984","volume":"2015","author":"V Cottignoli","year":"2015","unstructured":"Cottignoli, V., Cavarretta, E., Salvador, L., Valfre, C. & Maras, A. Morphological and chemical study of pathological deposits in human aortic and mitral valve stenosis: a biomineralogical contribution. Pathology Research International 2015, 342984 (2015).","journal-title":"Pathology Research International"},{"key":"32170_CR3","doi-asserted-by":"publisher","first-page":"1121","DOI":"10.1366\/12-06606","volume":"66","author":"S Mangialardo","year":"2012","unstructured":"Mangialardo, S. et al. Pathological biominerals: Raman and infrared studies of bioapatite deposits in human heart valves. Applied Spectroscopy 66, 1121\u20131127 (2012).","journal-title":"Applied Spectroscopy"},{"key":"32170_CR4","doi-asserted-by":"publisher","first-page":"138","DOI":"10.1093\/cvr\/cvs019","volume":"95","author":"C Fouillade","year":"2012","unstructured":"Fouillade, C., Monet-Lepretre, M., Baron-Menguy, C. & Joutel, A. Notch signalling in smooth muscle cells during development and disease. Cardiovascular Research 95, 138\u2013146 (2012).","journal-title":"Cardiovascular Research"},{"key":"32170_CR5","doi-asserted-by":"publisher","first-page":"2504","DOI":"10.1093\/eurheartj\/ehs141","volume":"34","author":"P Rizzo","year":"2013","unstructured":"Rizzo, P., Miele, L. & Ferrari, R. The Notch pathway: a crossroad between the life and death of the endothelium. European Heart Journal 34, 2504\u20132509 (2013).","journal-title":"European Heart Journal"},{"key":"32170_CR6","doi-asserted-by":"publisher","first-page":"50","DOI":"10.1016\/j.arr.2016.06.004","volume":"29","author":"CR Balistreri","year":"2016","unstructured":"Balistreri, C. R., Madonna, R., Melino, G. & Caruso, C. The emerging role of Notch pathway in ageing: Focus on the related mechanisms in age-related diseases. Ageing Research Reviews 29, 50\u201365 (2016).","journal-title":"Ageing Research Reviews"},{"key":"32170_CR7","doi-asserted-by":"publisher","first-page":"e001064","DOI":"10.1161\/JAHA.114.001064","volume":"3","author":"J Cheng","year":"2014","unstructured":"Cheng, J., Koenig, S. N., Kuivaniemi, H. S., Garg, V. & Hans, C. P. Pharmacological inhibitor of notch signaling stabilizes the progression of small abdominal aortic aneurysm in a mouse model. Journal of the American Heart Association 3, e001064 (2014).","journal-title":"Journal of the American Heart Association"},{"key":"32170_CR8","doi-asserted-by":"publisher","first-page":"3012","DOI":"10.1161\/ATVBAHA.112.254219","volume":"32","author":"CP Hans","year":"2012","unstructured":"Hans, C. P. et al. Inhibition of Notch1 signaling reduces abdominal aortic aneurysm in mice by attenuating macrophage-mediated inflammation. Arteriosclerosis, Thrombosis, and Vascular Biology 32, 3012\u20133023 (2012).","journal-title":"Arteriosclerosis, Thrombosis, and Vascular Biology"},{"key":"32170_CR9","doi-asserted-by":"publisher","first-page":"e52833","DOI":"10.1371\/journal.pone.0052833","volume":"7","author":"S Zou","year":"2012","unstructured":"Zou, S. et al. Notch signaling in descending thoracic aortic aneurysm and dissection. PloS One 7, e52833 (2012).","journal-title":"PloS One"},{"key":"32170_CR10","doi-asserted-by":"publisher","first-page":"409","DOI":"10.1161\/ATVBAHA.114.304849","volume":"35","author":"TL Henshall","year":"2015","unstructured":"Henshall, T. L. et al. Notch3 is necessary for blood vessel integrity in the central nervous system. Arteriosclerosis, Thrombosis, and Vascular Biology 35, 409\u2013420 (2015).","journal-title":"Arteriosclerosis, Thrombosis, and Vascular Biology"},{"key":"32170_CR11","doi-asserted-by":"publisher","first-page":"1072","DOI":"10.1016\/j.cell.2015.02.035","volume":"160","author":"CV Theodoris","year":"2015","unstructured":"Theodoris, C. V. et al. Human disease modeling reveals integrated transcriptional and epigenetic mechanisms of NOTCH1 haploinsufficiency. Cell 160, 1072\u20131086 (2015).","journal-title":"Cell"},{"key":"32170_CR12","doi-asserted-by":"publisher","first-page":"901","DOI":"10.1101\/gad.291004","volume":"18","author":"A Fischer","year":"2004","unstructured":"Fischer, A., Schumacher, N., Maier, M., Sendtner, M. & Gessler, M. The Notch target genes Hey1 and Hey2 are required for embryonic vascular. development. Genes & development 18, 901\u2013911 (2004).","journal-title":"development. Genes & development"},{"key":"32170_CR13","doi-asserted-by":"publisher","first-page":"1826","DOI":"10.1161\/01.CIR.0000160870.93058.DD","volume":"111","author":"FP Limbourg","year":"2005","unstructured":"Limbourg, F. P. et al. Essential role of endothelial Notch1 in angiogenesis. Circulation 111, 1826\u20131832 (2005).","journal-title":"Circulation"},{"key":"32170_CR14","doi-asserted-by":"publisher","first-page":"70","DOI":"10.1161\/01.RES.0000254788.47304.6e","volume":"100","author":"K Takeshita","year":"2007","unstructured":"Takeshita, K. et al. Critical role of endothelial Notch1 signaling in postnatal angiogenesis. Circulation Research 100, 70\u201378 (2007).","journal-title":"Circulation Research"},{"key":"32170_CR15","doi-asserted-by":"publisher","first-page":"158","DOI":"10.1016\/j.jtcvs.2012.09.060","volume":"146","author":"KC Kent","year":"2013","unstructured":"Kent, K. C., Crenshaw, M. L., Goh, D. L. & Dietz, H. C. Genotype-phenotype correlation in patients with bicuspid aortic valve and aneurysm. The Journal of Thoracic and Cardiovascular Surgery 146, 158\u2013165 e151 (2013).","journal-title":"The Journal of Thoracic and Cardiovascular Surgery"},{"key":"32170_CR16","doi-asserted-by":"publisher","first-page":"290","DOI":"10.1016\/j.jtcvs.2007.02.041","volume":"134","author":"SH McKellar","year":"2007","unstructured":"McKellar, S. H. et al. Novel NOTCH1 mutations in patients with bicuspid aortic valve disease and thoracic aortic aneurysms. The Journal of Thoracic and Cardiovascular Surgery 134, 290\u2013296 (2007).","journal-title":"The Journal of Thoracic and Cardiovascular Surgery"},{"key":"32170_CR17","doi-asserted-by":"publisher","first-page":"157","DOI":"10.1161\/CIRCULATIONAHA.107.754978","volume":"118","author":"SM Kwon","year":"2008","unstructured":"Kwon, S. M. et al. Specific Jagged-1 signal from bone marrow microenvironment is required for endothelial progenitor cell development for neovascularization. Circulation 118, 157\u2013165 (2008).","journal-title":"Circulation"},{"key":"32170_CR18","doi-asserted-by":"publisher","first-page":"e7572","DOI":"10.1371\/journal.pone.0007572","volume":"4","author":"L Wang","year":"2009","unstructured":"Wang, L. et al. Notch-RBP-J signaling regulates the mobilization and function of endothelial progenitor cells by dynamic modulation of CXCR4 expression in mice. PloS One 4, e7572 (2009).","journal-title":"PloS One"},{"key":"32170_CR19","doi-asserted-by":"publisher","first-page":"1070","DOI":"10.1016\/j.ijcard.2012.11.002","volume":"168","author":"SH Sung","year":"2013","unstructured":"Sung, S. H. et al. Reduced number and impaired function of circulating endothelial progenitor cells in patients with abdominal aortic aneurysm. International Journal of Cardiology 168, 1070\u20131077 (2013).","journal-title":"International Journal of Cardiology"},{"key":"32170_CR20","doi-asserted-by":"publisher","first-page":"1822","DOI":"10.1002\/jnr.22696","volume":"89","author":"H Wei","year":"2011","unstructured":"Wei, H. et al. Changes and function of circulating endothelial progenitor cells in patients with cerebral aneurysm. Journal of Neuroscience Research 89, 1822\u20131828 (2011).","journal-title":"Journal of Neuroscience Research"},{"key":"32170_CR21","doi-asserted-by":"publisher","first-page":"10089","DOI":"10.1074\/jbc.M600298200","volume":"281","author":"A Miyamoto","year":"2006","unstructured":"Miyamoto, A., Lau, R., Hein, P. W., Shipley, J. M. & Weinmaster, G. Microfibrillar proteins MAGP-1 and MAGP-2 induce Notch1 extracellular domain dissociation and receptor activation. Journal of Biology Chemestry 281, 10089\u201397 (2006).","journal-title":"Journal of Biology Chemestry"},{"key":"32170_CR22","doi-asserted-by":"publisher","first-page":"e10532","DOI":"10.1371\/journal.pone.0010532","volume":"5","author":"DF Kelly","year":"2010","unstructured":"Kelly, D. F. et al. Molecular structure and dimeric organization of the Notch extracellular domain as revealed by electron microscopy. PLoS One 5, e10532 (2010).","journal-title":"PLoS One"},{"key":"32170_CR23","doi-asserted-by":"publisher","first-page":"e36362","DOI":"10.1371\/journal.pone.0036362","volume":"7","author":"G Xie","year":"2012","unstructured":"Xie, G. et al. Uif, a large transmembrane protein with EGF-like repeats, can antagonize Notch signaling in Drosophila. PLoS One 7, e36362 (2012).","journal-title":"PLoS One"},{"key":"32170_CR24","doi-asserted-by":"publisher","first-page":"228","DOI":"10.1016\/j.devcel.2017.04.001","volume":"41","author":"RA Kovall","year":"2017","unstructured":"Kovall, R. A., Gebelein, B., Sprinzak, D. & Kopan, R. The Canonical Notch Signaling Pathway: Structural and Biochemical Insights into Shape, Sugar, and Force. Developmental Cell 41, 228\u2013241 (2017).","journal-title":"Developmental Cell"},{"key":"32170_CR25","doi-asserted-by":"publisher","first-page":"835934","DOI":"10.1155\/2015\/835934","volume":"2015","author":"CR Balistreri","year":"2015","unstructured":"Balistreri, C. R., Buffa, S., Pisano, C., Lio, D., Ruvolo, G. & Mazzesi, G. Are Endothelial Progenitor Cells the Real Solution for Cardiovascular Diseases? Focus on Controversies and Perspectives. BioMed research international 2015, 835934 (2015).","journal-title":"BioMed research international"},{"key":"32170_CR26","unstructured":"Balistrieri, C. Endothelial progenitor cells: a new real hope or only an unrealizable dream? Springer International Publishing, Dordrecht pgg. 1\u201380 (2017)."},{"key":"32170_CR27","doi-asserted-by":"publisher","first-page":"1392","DOI":"10.1161\/CIRCRESAHA.116.305368","volume":"116","author":"PJ Psaltis","year":"2015","unstructured":"Psaltis, P. J. & Simari, R. D. Vascular wall progenitor cells in health and disease. Circulation Research 116, 1392\u20131412 (2015).","journal-title":"Circulation Research"},{"key":"32170_CR28","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1016\/j.yjmcc.2017.06.011","volume":"110","author":"CR Balistreri","year":"2017","unstructured":"Balistreri, C. R., Ruvolo, G., Lio, D. & Madonna, R. Toll-like receptor-4 signaling pathway in aorta ageing and diseases: \u201cits double nature\u201d. Journal of Molecular and Cellular Cardiology 110, 38\u201353 (2017).","journal-title":"Journal of Molecular and Cellular Cardiology"},{"key":"32170_CR29","first-page":"1004","volume":"1","author":"CR Balistreri","year":"2018","unstructured":"Balistreri, C. R. Bicuspid aortic valve disease: a simple embryonic defect or a complex syndrome? Paradigm or certainty? Annals of Cardiol ogy and Vascular Medicine 1, 1004 (2018).","journal-title":"Annals of Cardiol ogy and Vascular Medicine"},{"key":"32170_CR30","doi-asserted-by":"publisher","first-page":"e180","DOI":"10.1093\/ejcts\/ezs630","volume":"43","author":"CR Balistreri","year":"2013","unstructured":"Balistreri, C. R. et al. Focus on the unique mechanisms involved in thoracic aortic aneurysm formation in bicuspid aortic valve versus tricuspid aortic valve patients: clinical implications of a pilot study. European journal of Cardio-thoracic Surgery 43, e180\u2013186 (2013).","journal-title":"European journal of Cardio-thoracic Surgery"},{"key":"32170_CR31","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.vph.2015.09.006","volume":"74","author":"CR Balistreri","year":"2015","unstructured":"Balistreri, C. R. Genetic contribution in sporadic thoracic aortic aneurysm? Emerging evidence of genetic variants related to TLR-4-mediated signaling pathway as risk determinants. Vascular pharmacology 74, 1\u201310 (2015).","journal-title":"Vascular pharmacology"},{"key":"32170_CR32","doi-asserted-by":"publisher","first-page":"349476","DOI":"10.1155\/2014\/349476","volume":"2014","author":"G Ruvolo","year":"2014","unstructured":"Ruvolo, G. et al. Can the TLR-4-mediated signaling pathway be \u201ca key inflammatory promoter for sporadic AAA\u201d? Mediators of Inflammation 2014, 349476 (2014).","journal-title":"Mediators of Inflammation"},{"key":"32170_CR33","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1016\/S1010-7940(01)01037-5","volume":"21","author":"E Prifti","year":"2002","unstructured":"Prifti, E. et al. Early and long-term outcome in patients undergoing aortic root replacement with composite graft according to the Bentall\u2019s technique. European of Journal of Cardiothoracic Surgery 21, 15\u201321 (2002).","journal-title":"European of Journal of Cardiothoracic Surgery"},{"key":"32170_CR34","doi-asserted-by":"publisher","first-page":"e13790","DOI":"10.1371\/journal.pone.0013790","volume":"5","author":"C Schmidt-Lucke","year":"2010","unstructured":"Schmidt-Lucke, C. et al. Quantification of circulating endothelial progenitor cells using the modified ISHAGE protocol. PloS one 5, e13790 (2010).","journal-title":"PloS one"},{"key":"32170_CR35","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1089\/scd.1.1996.5.213","volume":"5","author":"DR Sutherland","year":"1996","unstructured":"Sutherland, D. R., Anderson, L., Keeney, M., Nayar, R. & Chin-Yee, I. The ISHAGE guidelines for CD34+ cell determination by flow cytometry. International Society of Hematotherapy and Graft Engineering. Journal of Hematotherapy 5, 213\u2013226 (1996).","journal-title":"Journal of Hematotherapy"},{"key":"32170_CR36","doi-asserted-by":"publisher","DOI":"10.1186\/gb-2002-3-7-research0034","volume":"3","author":"J Vandesompele","year":"2002","unstructured":"Vandesompele, J. et al. Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biology 3, RESEARCH0034 (2002).","journal-title":"Genome Biology"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-018-32170-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-018-32170-2","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-018-32170-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,21]],"date-time":"2022-12-21T09:33:15Z","timestamp":1671615195000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-018-32170-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,9,14]]},"references-count":36,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2018,12]]}},"alternative-id":["32170"],"URL":"https:\/\/doi.org\/10.1038\/s41598-018-32170-2","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,9,14]]},"assertion":[{"value":"22 June 2018","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"30 August 2018","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 September 2018","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"13834"}}