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However, little is known about its underlying mechanisms due to the lack of validated animal models. The present study developed a mouse model that may be utilized to investigate exacerbation of TAAD formation by mimetics of tobacco smoke. TAADs were created via inducible deletion of smooth muscle cell-specific Tgfbr2 receptors. Using this model, the first set of experiments evaluated the efficacy of nicotine salt (34.0\u2009mg\/kg\/day), nicotine free base (NFB, 5.0\u2009mg 90-day pellets), and cigarette smoke extract (0.1\u2009ml\/mouse\/day). Compared with their respective control groups, only NFB pellets promoted TAAD dilation (<jats:inline-formula>\n                     <a:math xmlns:a=\"http:\/\/www.w3.org\/1998\/Math\/MathML\" id=\"M1\">\n                        <a:mn>23<\/a:mn>\n                        <a:mo>\u00b1<\/a:mo>\n                        <a:mn>3<\/a:mn>\n                        <a:mi>%<\/a:mi>\n                     <\/a:math>\n                  <\/jats:inline-formula> vs. <jats:inline-formula>\n                     <c:math xmlns:c=\"http:\/\/www.w3.org\/1998\/Math\/MathML\" id=\"M2\">\n                        <c:mn>12<\/c:mn>\n                        <c:mo>\u00b1<\/c:mo>\n                        <c:mn>2<\/c:mn>\n                        <c:mi>%<\/c:mi>\n                     <\/c:math>\n                  <\/jats:inline-formula>, <jats:inline-formula>\n                     <e:math xmlns:e=\"http:\/\/www.w3.org\/1998\/Math\/MathML\" id=\"M3\">\n                        <e:mi>P<\/e:mi>\n                        <e:mo>=<\/e:mo>\n                        <e:mn>0.014<\/e:mn>\n                     <\/e:math>\n                  <\/jats:inline-formula>), and this efficacy was achieved at a cost of &gt;50% acute mortality. Infusion of NFB with osmotic minipumps at extremely high, but nonlethal, doses (15.0 or 45.0\u2009mg\/kg\/day) failed to accelerate TAAD dilation. Interestingly, costimulation with \u03b2-aminopropionitrile (BAPN) promoted TAAD dilation and aortic rupture at dosages of 3.0 and 45.0\u2009mg\/kg\/day, respectively, indicating that BAPN sensitizes the response of TAADs to NFB. In subsequent analyses, the detrimental effects of NFB were associated with clustering of macrophages, neutrophils, and T-cells in areas with structural destruction, enhanced matrix metalloproteinase- (MMP-) 2 production, and pathological angiogenesis with attenuated fibrosis in the adventitia. In conclusion, modeling nicotine exacerbation of TAAD formation requires optimization of chemical form, route of delivery, and dosage of the drug as well as the pathologic complexity of TAADs. Under the optimized conditions of the present study, chronic inflammation and adventitial mal-remodeling serve as critical pathways through which NFB exacerbates TAAD formation.<\/jats:p>","DOI":"10.1155\/2021\/6880036","type":"journal-article","created":{"date-parts":[[2021,10,1]],"date-time":"2021-10-01T22:52:14Z","timestamp":1633128734000},"page":"1-17","source":"Crossref","is-referenced-by-count":10,"title":["Nicotine Exacerbates TAAD Formation Induced by Smooth Muscle-Specific Deletion of the TGF-\u03b2 Receptor 2"],"prefix":"10.1155","volume":"2021","author":[{"given":"Changzoon","family":"Chun","sequence":"first","affiliation":[{"name":"Division of Vascular Surgery and Endovascular Therapy, University of Florida College of Medicine, Gainesville, FL 32603, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaoyan","family":"Qi","sequence":"additional","affiliation":[{"name":"Division of Vascular Surgery and Endovascular Therapy, University of Florida College of Medicine, Gainesville, FL 32603, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fen","family":"Wang","sequence":"additional","affiliation":[{"name":"Division of Vascular Surgery and Endovascular Therapy, University of Florida College of Medicine, Gainesville, FL 32603, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kyle B.","family":"Madrid","sequence":"additional","affiliation":[{"name":"Division of Vascular Surgery and Endovascular Therapy, University of Florida College of Medicine, Gainesville, FL 32603, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lennon A.","family":"Saldarriaga","sequence":"additional","affiliation":[{"name":"Division of Vascular Surgery and Endovascular Therapy, University of Florida College of Medicine, Gainesville, FL 32603, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Max R.","family":"Fisch","sequence":"additional","affiliation":[{"name":"Division of Vascular Surgery and Endovascular Therapy, University of Florida College of Medicine, Gainesville, FL 32603, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mark L.","family":"Brantly","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Florida College of Medicine, Gainesville, FL 32603, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"suffix":"Jr.","given":"Gilbert R.","family":"Upchurch","sequence":"additional","affiliation":[{"name":"Division of Vascular Surgery and Endovascular Therapy, University of Florida College of Medicine, Gainesville, FL 32603, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8057-823X","authenticated-orcid":true,"given":"Zhihua","family":"Jiang","sequence":"additional","affiliation":[{"name":"Division of Vascular Surgery and Endovascular Therapy, University of Florida College of Medicine, Gainesville, FL 32603, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","reference":[{"key":"1","doi-asserted-by":"publisher","DOI":"10.12945\/j.aorta.2013.13-043"},{"key":"2","doi-asserted-by":"publisher","DOI":"10.1136\/openhrt-2014-000169"},{"key":"3","doi-asserted-by":"publisher","DOI":"10.1530\/ERP-19-0049"},{"key":"4","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.117.311075"},{"key":"5","article-title":"Risk profiles for aortic dissection and ruptured or surgically treated aneurysms: a prospective cohort study","volume":"4, article e001513","author":"M. 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