{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T13:07:30Z","timestamp":1788786450505,"version":"build-2803163510"},"reference-count":45,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2023,9,1]],"date-time":"2023-09-01T00:00:00Z","timestamp":1693526400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH","award":["1R01HL165471-01"],"award-info":[{"award-number":["1R01HL165471-01"]}]},{"name":"NIH","award":["R00HL128787"],"award-info":[{"award-number":["R00HL128787"]}]},{"DOI":"10.13039\/100005831","name":"Foundation for Anesthesia Education and Research","doi-asserted-by":"publisher","award":["MRTG-02-15-2021"],"award-info":[{"award-number":["MRTG-02-15-2021"]}],"id":[{"id":"10.13039\/100005831","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Marfan syndrome causes a hereditary form of thoracic aortic aneurysms with worse outcomes in male compared to female patients. In this study, we examine the effects of 17 \u03b2-estradiol on aortic dilation and rupture in a Marfan mouse model. Marfan male mice were administered 17 \u03b2-estradiol, and the growth in the aortic root, along with the risk of aortic rupture, was measured. Transcriptomic profiling was used to identify enriched pathways from 17 \u03b2-estradiol treatments. Aortic smooth muscle cells were then treated with cytokines to validate functional mechanisms. We show that 17 \u03b2-estradiol decreased the size and rate of aortic root dilation and improved survival from rupture. The Marfan transcriptome was enriched in inflammatory genes, and the addition of 17 \u03b2-estradiol modulated a set of genes that function through TNF\u03b1 mediated NF-\u03baB signaling. In addition, 17 \u03b2-estradiol suppressed the induction of these TNF\u03b1 induced genes in aortic smooth muscle cells in vitro in an NF-\u03baB dependent manner, and 17 \u03b2-estradiol decreased the formation of adventitial inflammatory foci in aortic roots in vivo. In conclusion, 17 \u03b2-estradiol protects against the dilation and rupture of aortic roots in Marfan male mice through the inhibition of TNF\u03b1-NF-\u03baB signaling.<\/jats:p>","DOI":"10.3390\/ijms241713571","type":"journal-article","created":{"date-parts":[[2023,9,1]],"date-time":"2023-09-01T08:19:39Z","timestamp":1693556379000},"page":"13571","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["17 \u03b2-Estradiol Impedes Aortic Root Dilation and Rupture in Male Marfan Mice"],"prefix":"10.3390","volume":"24","author":[{"given":"Louis","family":"Saddic","sequence":"first","affiliation":[{"name":"Department of Anesthesiology and Perioperative Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sean","family":"Escopete","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lior","family":"Zilberberg","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shannon","family":"Kalsow","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Divya","family":"Gupta","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mansoureh","family":"Eghbali","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Perioperative Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Parker","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,9,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e27","DOI":"10.1016\/j.jacc.2010.02.015","article-title":"2010 ACCF\/AHA\/AATS\/ACR\/ASA\/SCA\/SCAI\/SIR\/STS\/SVM Guidelines for the diagnosis and management of patients with thoracic aortic disease. A Report of the American College of Cardiology Foundation\/American Heart Association Task Force on Practice Guidelines, American Association for Thoracic Surgery, American College of Radiology, American Stroke Association, Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, Society of Interventional Radiology, Society of Thoracic Surgeons, and Society for Vascular Medicine","volume":"55","author":"Hiratzka","year":"2010","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e003792","DOI":"10.1161\/JAHA.116.003792","article-title":"Thoracic Aortic Aneurysm Growth: Role of Sex and Aneurysm Etiology","volume":"6","author":"Cheung","year":"2017","journal-title":"J. Am. Heart Assoc."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1053\/j.semtcvs.2011.08.009","article-title":"Sex and gender in thoracic aortic aneurysms and dissection","volume":"23","author":"Grubb","year":"2011","journal-title":"Semin. Thorac. Cardiovasc. Surg."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2116","DOI":"10.1161\/01.ATV.0000143386.26399.84","article-title":"Gender differences in experimental aortic aneurysm formation","volume":"24","author":"Ailawadi","year":"2004","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1627","DOI":"10.1161\/01.ATV.0000085842.20866.6A","article-title":"B-Estradiol Attenuates Development of Angiotensin II Induced Aortic Abdominal Aneurysm in Apolipoprotein E Deficient Mice","volume":"23","author":"Tham","year":"2003","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Chen, X., Rateri, D.L., Howatt, D.A., Balakrishnan, A., Moorleghen, J.J., Cassis, L.A., and Daugherty, A. (2016). TGF-\u03b2 Neutralization Enhances AngII-Induced Aortic Rupture and Aneurysm in Both Thoracic and Abdominal Regions. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0153811"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1007\/s00392-016-1028-3","article-title":"Aortic events in a nationwide Marfan syndrome cohort","volume":"106","author":"Groth","year":"2017","journal-title":"Clin. Res. Cardiol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"H44","DOI":"10.1152\/ajpheart.00255.2021","article-title":"Age and sex dependency of thoracic aortopathy in a mouse model of Marfan syndrome","volume":"322","author":"Gharraee","year":"2022","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"933","DOI":"10.3389\/fphys.2017.00933","article-title":"Differences in the Thoracic Aorta by Region and Sex in a Murine Model of Marfan Syndrome","volume":"8","author":"Siegert","year":"2017","journal-title":"Front. Physiol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1400","DOI":"10.1016\/j.athoracsur.2006.04.098","article-title":"Familial thoracic aortic aneurysms and dissections--incidence, modes of inheritance, and phenotypic patterns","volume":"82","author":"Albornoz","year":"2006","journal-title":"Ann. Thorac. Surg."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"e015773","DOI":"10.1161\/JAHA.119.015773","article-title":"Androgens Accentuate TGF-\u03b2 Dependent Erk\/Smad Activation During Thoracic Aortic Aneurysm Formation in Marfan Syndrome Male Mice","volume":"9","author":"Tashima","year":"2020","journal-title":"J. Am. Heart Assoc."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"H416","DOI":"10.1152\/ajpheart.00865.2005","article-title":"Flutamide restores cardiac function after trauma-hemorrhage via an estrogen-dependent pathway through upregulation of PGC-1","volume":"290","author":"Hsieh","year":"2006","journal-title":"Am. J. Physiology. Heart Circ. Physiol."},{"key":"ref_13","first-page":"1147","article-title":"Androgen receptor blockade with flutamide enhances growth hormone secretion in late pubertal males: Evidence for independent actions of estrogen and androgen","volume":"76","author":"Metzger","year":"1993","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"H524","DOI":"10.1152\/ajpheart.00217.2016","article-title":"Sex differences in vascular physiology and pathophysiology: Estrogen and androgen signaling in health and disease","volume":"313","author":"Boese","year":"2017","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1161\/ATVBAHA.108.182279","article-title":"Estrogen and Mechanisms of Vascular Protection","volume":"29","author":"Xing","year":"2009","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"987","DOI":"10.1161\/01.ATV.0000214999.12921.4f","article-title":"Inflammation and Cellular Immune Responses in Abdominal Aortic Aneurysms","volume":"26","author":"Shimizu","year":"2006","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"922","DOI":"10.1016\/j.jtcvs.2007.12.063","article-title":"Characterization of the inflammatory cells in ascending thoracic aortic aneurysms in patients with Marfan syndrome, familial thoracic aortic aneurysms, and sporadic aneurysms","volume":"136","author":"He","year":"2008","journal-title":"J. Thorac. Cardiovasc. Surg."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1855","DOI":"10.1161\/CIRCULATIONAHA.105.601674","article-title":"Induction of Macrophage Chemotaxis by Aortic Extracts of the mgR Marfan Mouse Model and a GxxPG-Containing Fibrillin-1 Fragment","volume":"114","author":"Guo","year":"2006","journal-title":"Circulation"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1016\/j.athoracsur.2016.10.077","article-title":"A Novel Murine Model of Marfan Syndrome Accelerates Aortopathy and Cardiomyopathy","volume":"104","author":"Cavanaugh","year":"2017","journal-title":"Ann. Thorac. Surg."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"H2607","DOI":"10.1152\/ajpheart.01107.2006","article-title":"Estrogen modulates TNF-alpha-induced inflammatory responses in rat aortic smooth muscle cells through estrogen receptor-beta activation","volume":"292","author":"Xing","year":"2007","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.maturitas.2016.11.005","article-title":"Differential expression of sex hormone receptors in abdominal aortic aneurysms","volume":"96","author":"Villard","year":"2017","journal-title":"Maturitas"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1016\/j.jmbbm.2014.02.015","article-title":"Impaired mechanics and matrix metalloproteinases\/inhibitors expression in female ascending thoracic aortic aneurysms","volume":"34","author":"Sokolis","year":"2014","journal-title":"J. Mech. Behav. Biomed. Mater."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Xing, D., Oparil, S., Yu, H., Gong, K., Feng, W., Black, J., Chen, Y.F., and Nozell, S. (2012). Estrogen modulates NF\u03baB signaling by enhancing I\u03baB\u03b1 levels and blocking p65 binding at the promoters of inflammatory genes via estrogen receptor-\u03b2. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0036890"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2957","DOI":"10.1128\/MCB.25.8.2957-2968.2005","article-title":"17beta-estradiol inhibits inflammatory gene expression by controlling NF-kappaB intracellular localization","volume":"25","author":"Ghisletti","year":"2005","journal-title":"Mol. Cell Biol."},{"key":"ref_25","first-page":"4009","article-title":"PKCtheta promotes c-Rel-driven mammary tumorigenesis in mice and humans by repressing estrogen receptor alpha synthesis","volume":"117","author":"Belguise","year":"2007","journal-title":"J. Clin. Investig."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1134","DOI":"10.1161\/ATVBAHA.122.318448","article-title":"Lineage-Specific Induced Pluripotent Stem Cell-Derived Smooth Muscle Cell Modeling Predicts Integrin Alpha-V Antagonism Reduces Aortic Root Aneurysm Formation in Marfan Syndrome Mice","volume":"43","author":"Nakamura","year":"2023","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1152\/physiolgenomics.00160.2011","article-title":"Interleukin-1\u03b2 modulates smooth muscle cell phenotype to a distinct inflammatory state relative to PDGF-DD via NF-\u03baB-dependent mechanisms","volume":"44","author":"Alexander","year":"2012","journal-title":"Physiol. Genom."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1564","DOI":"10.1038\/jcbfm.2013.109","article-title":"TNF-\u03b1 induces phenotypic modulation in cerebral vascular smooth muscle cells: Implications for cerebral aneurysm pathology","volume":"33","author":"Ali","year":"2013","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1186\/s12964-022-00993-2","article-title":"How vascular smooth muscle cell phenotype switching contributes to vascular disease","volume":"20","author":"Cao","year":"2022","journal-title":"Cell Commun. Signal."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1016\/j.jvs.2004.12.030","article-title":"Suppression of experimental abdominal aortic aneurysms in mice by treatment with pyrrolidine dithiocarbamate, an antioxidant inhibitor of nuclear factor-kappaB","volume":"41","author":"Parodi","year":"2005","journal-title":"J. Vasc. Surg."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1161\/CIRCRESAHA.116.309322","article-title":"Differentiated Smooth Muscle Cells Generate a Subpopulation of Resident Vascular Progenitor Cells in the Adventitia Regulated by Klf4","volume":"120","author":"Majesky","year":"2017","journal-title":"Circ. Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1719","DOI":"10.1016\/j.jtcvs.2019.05.043","article-title":"Accelerated Marfan syndrome model recapitulates established signaling pathways","volume":"159","author":"Gensicke","year":"2020","journal-title":"J. Thorac. Cardiovasc. Surg."},{"key":"ref_33","first-page":"7806409","article-title":"Identification of Vinculin as a Potential Diagnostic Biomarker for Acute Aortic Dissection Using Label-Free Proteomics","volume":"2020","author":"Wang","year":"2020","journal-title":"BioMed Res. Int."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1172\/JCI123547","article-title":"Lineage-specific events underlie aortic root aneurysm pathogenesis in Loeys-Dietz syndrome","volume":"129","author":"MacFarlane","year":"2019","journal-title":"J. Clin. Investig."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1186\/1749-8090-8-83","article-title":"Isolation and culture of smooth muscle cells from human acute type A aortic dissection","volume":"8","author":"Lu","year":"2013","journal-title":"J. Cardiothorac. Surg."},{"key":"ref_36","unstructured":"(2022, December 01). FastQC: A Quality Control Tool for High Throughput Sequence Data. Available online: http:\/\/www.bioinformatics.babraham.ac.uk\/projects\/fastqc."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"R36","DOI":"10.1186\/gb-2013-14-4-r36","article-title":"TopHat2: Accurate alignment of transcriptomes in the presence of insertions, deletions and gene fusions","volume":"14","author":"Kim","year":"2013","journal-title":"Genome Biol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2943","DOI":"10.1093\/bioinformatics\/btac166","article-title":"Analysing high-throughput sequencing data in Python with HTSeq 2.0","volume":"38","author":"Putri","year":"2022","journal-title":"Bioinformatics"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1186\/s13059-014-0550-8","article-title":"Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2","volume":"15","author":"Love","year":"2014","journal-title":"Genome Biol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"15545","DOI":"10.1073\/pnas.0506580102","article-title":"Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles","volume":"102","author":"Subramanian","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_41","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_42","doi-asserted-by":"crossref","first-page":"2628","DOI":"10.1093\/bioinformatics\/btz931","article-title":"ShinyGO: A graphical gene-set enrichment tool for animals and plants","volume":"36","author":"Ge","year":"2019","journal-title":"Bioinformatics"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Wickham, H. (2016). ggplot2: Elegant Graphics for Data Analysis, Springer.","DOI":"10.1007\/978-3-319-24277-4"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1038\/nmeth.2089","article-title":"NIH Image to ImageJ: 25 years of image analysis","volume":"9","author":"Schneider","year":"2012","journal-title":"Nat. Methods"},{"key":"ref_45","unstructured":"RStudio Team (2019). RStudio: Integrated Development for R, RStudio Team."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/17\/13571\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T20:44:54Z","timestamp":1760129094000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/17\/13571"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,9,1]]},"references-count":45,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2023,9]]}},"alternative-id":["ijms241713571"],"URL":"https:\/\/doi.org\/10.3390\/ijms241713571","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,9,1]]}}}