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However, the etiology and molecular events downstream of\n              <jats:styled-content style=\"fixed-case\">SMAD<\/jats:styled-content>\n              3 leading to the pathogenesis of aortic aneurysms in these patients still remain elusive. Therefore, we aimed to investigate the vascular phenotypes of\n              <jats:italic>\n                <jats:styled-content style=\"fixed-case\">SMAD<\/jats:styled-content>\n              <\/jats:italic>\n              3\u2010knockout mice.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Methods and Results<\/jats:title>\n            <jats:p xml:lang=\"en\">\n              We have shown that angiotensin II\u2013induced vascular inflammation, but not hypertension, leads to aortic aneurysms and dissections, ultimately causing aortic rupture and death in mice. Lipopolysaccharide\u2010triggered inflammation confirmed that enhanced aortic macrophage recruitment was essential for aneurysm formation in angiotensin II\u2013infused\n              <jats:italic>SMAD3<\/jats:italic>\n              \u2010knockout mice. In contrast, phenylephrine\u2010triggered hypertension alone was insufficient to induce aortic aneurysms in mice. Using uniaxial tensile and contractility tests, we showed that SMAD3 deficiency resulted in defective aortic biomechanics and physiological functions, which caused weakening of the aortic wall and predisposed the mice to aortic aneurysms. Chromatin immunoprecipitation (ChIP) and re\u2010ChIP assays revealed that the underlying mechanism involved aberrant upregulation of inducible nitric oxide synthase (\n              <jats:styled-content style=\"fixed-case\">iNOS<\/jats:styled-content>\n              )\u2013derived nitric oxide production and activation of elastolytic matrix metalloproteinases 2 and 9. Administration of clodronate\u2010liposomes and\n              <jats:styled-content style=\"fixed-case\">iNOS<\/jats:styled-content>\n              inhibitor completely abrogated these aortic conditions, thereby identifying\n              <jats:styled-content style=\"fixed-case\">iNOS<\/jats:styled-content>\n              \u2010mediated nitric oxide secretion from macrophages as the downstream event of SMAD3 that drives this severe pathology.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p xml:lang=\"en\">\n              Macrophage depletion and\n              <jats:styled-content style=\"fixed-case\">iNOS<\/jats:styled-content>\n              antagonism represent 2 promising approaches for preventing aortic aneurysms related to\n              <jats:italic>SMAD3<\/jats:italic>\n              mutations and merit further investigation as adjunctive strategies for the life\u2010threatening manifestations of AOS.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/jaha.113.000269","type":"journal-article","created":{"date-parts":[[2013,6,20]],"date-time":"2013-06-20T03:56:20Z","timestamp":1371700580000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":49,"title":["SMAD3 Deficiency Promotes Inflammatory Aortic Aneurysms in Angiotensin II\u2013Infused Mice Via Activation of iNOS"],"prefix":"10.1161","volume":"2","author":[{"given":"Chek K.","family":"Tan","sequence":"first","affiliation":[{"name":"School of Biological Sciences, Nanyang Technological University, Nanyang, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eddie H.","family":"Tan","sequence":"additional","affiliation":[{"name":"School of Biological Sciences, Nanyang Technological University, Nanyang, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Baiwen","family":"Luo","sequence":"additional","affiliation":[{"name":"School of Materials Science and Engineering, Nanyang Technological University, Nanyang, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charlotte L.","family":"Huang","sequence":"additional","affiliation":[{"name":"School of Materials Science and Engineering, Nanyang Technological University, Nanyang, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joachim S.","family":"Loo","sequence":"additional","affiliation":[{"name":"School of Materials Science and Engineering, Nanyang Technological University, Nanyang, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cleo","family":"Choong","sequence":"additional","affiliation":[{"name":"School of Materials Science and Engineering, Nanyang Technological University, Nanyang, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nguan S.","family":"Tan","sequence":"additional","affiliation":[{"name":"School of Biological Sciences, Nanyang Technological University, Nanyang, Singapore"},{"name":"Institute of Molecular and Cell Biology, Proteos A*STAR, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1196\/annals.1383.013"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.v13.i22.3056"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.111.248161"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.744"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1136\/jmedgenet-2011-100382"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.153.1.35"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/18.5.1280"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.90.8.3491"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20040995"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.2337\/db10-0801"},{"key":"e_1_3_4_12_2","first-page":"1291","article-title":"Measuring blood pressure in mice using volume pressure recording, a tail\u2010cuff method","volume":"27","author":"Daugherty A","year":"2009","unstructured":"Daugherty A, Rateri D, Hong L, Balakrishnan A. 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