{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T00:07:52Z","timestamp":1791331672895,"version":"4.3.1"},"reference-count":51,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"3","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2016,2,5]]},"abstract":"<jats:sec>\n            <jats:title>\n              <jats:underline>Rationale:<\/jats:underline>\n            <\/jats:title>\n            <jats:p>Aortic aneurysm is a life-threatening cardiovascular disorder caused by the predisposition for dissection and rupture. Genetic studies have proved the involvement of the transforming growth factor-\u03b2 (TGF-\u03b2) pathway in aortic aneurysm. Smad4 is the central mediator of the canonical TGF-\u03b2 signaling pathway. However, the exact role of Smad4 in smooth muscle cells (SMCs) leading to the pathogenesis of aortic aneurysms is largely unknown.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>\n              <jats:underline>Objective:<\/jats:underline>\n            <\/jats:title>\n            <jats:p>To determine the role of smooth muscle Smad4 in the pathogenesis of aortic aneurysms.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>\n              <jats:underline>Methods and Results:<\/jats:underline>\n            <\/jats:title>\n            <jats:p>Conditional gene knockout strategy combined with histology and expression analysis showed that Smad4 or TGF-\u03b2 receptor type II deficiency in SMCs led to the occurrence of aortic aneurysms along with an upregulation of cathepsin S and matrix metallopeptidase-12, which are proteases essential for elastin degradation. We further demonstrated a previously unknown downregulation of matrix metallopeptidase-12 by TGF-\u03b2 in the aortic SMCs, which is largely abrogated in the absence of Smad4. Chemotactic assay and pharmacologic treatment demonstrated that Smad4-deficient SMCs directly triggered aortic wall inflammation via the excessive production of chemokines to recruit macrophages. Monocyte\/macrophage depletion or blocking selective chemokine axis largely abrogated the progression of aortic aneurysm caused by Smad4 deficiency in SMCs.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>\n              <jats:underline>Conclusions:<\/jats:underline>\n            <\/jats:title>\n            <jats:p>The findings reveal that Smad4-dependent TGF-\u03b2 signaling in SMCs protects against aortic aneurysm formation and dissection. The data also suggest important implications for novel therapeutic strategies to limit the progression of the aneurysm resulting from TGF-\u03b2 signaling loss-of-function mutations.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circresaha.115.308040","type":"journal-article","created":{"date-parts":[[2016,2,4]],"date-time":"2016-02-04T21:18:11Z","timestamp":1454620691000},"page":"388-399","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":91,"title":["Smad4 Deficiency in Smooth Muscle Cells Initiates the Formation of Aortic Aneurysm"],"prefix":"10.1161","volume":"118","author":[{"given":"Peng","family":"Zhang","sequence":"first","affiliation":[{"name":"From the State Key Laboratory of Proteomics, Collaborative Innovation Center for Cardiovascular Disorders, Genetic Laboratory of Development and Diseases, Institute of Biotechnology, Beijing, PR China (P.Z., S.H., J.C., J.Z., F.L., R.J., X.C., Y.L., X.Y.); Model Organism Division, E-institutes of Shanghai Universities, Shanghai Jiaotong University, Shanghai, PR China (P.Z., J.C., X.Y.); Institute of Vascular Medicine, Peking University Third Hospital and Key Laboratory of Molecular Cardiovascular..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siyuan","family":"Hou","sequence":"additional","affiliation":[{"name":"From the State Key Laboratory of Proteomics, Collaborative Innovation Center for Cardiovascular Disorders, Genetic Laboratory of Development and Diseases, Institute of Biotechnology, Beijing, PR China (P.Z., S.H., J.C., J.Z., F.L., R.J., X.C., Y.L., X.Y.); Model Organism Division, E-institutes of Shanghai Universities, Shanghai Jiaotong University, Shanghai, PR China (P.Z., J.C., X.Y.); Institute of Vascular Medicine, Peking University Third Hospital and Key Laboratory of Molecular Cardiovascular..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jicheng","family":"Chen","sequence":"additional","affiliation":[{"name":"From the State Key Laboratory of Proteomics, Collaborative Innovation Center for Cardiovascular Disorders, Genetic Laboratory of Development and Diseases, Institute of Biotechnology, Beijing, PR China (P.Z., S.H., J.C., J.Z., F.L., R.J., X.C., Y.L., X.Y.); Model Organism Division, E-institutes of Shanghai Universities, Shanghai Jiaotong University, Shanghai, PR China (P.Z., J.C., X.Y.); Institute of Vascular Medicine, Peking University Third Hospital and Key Laboratory of Molecular Cardiovascular..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jishuai","family":"Zhang","sequence":"additional","affiliation":[{"name":"From the State Key Laboratory of Proteomics, Collaborative Innovation Center for Cardiovascular Disorders, Genetic Laboratory of Development and Diseases, Institute of Biotechnology, Beijing, PR China (P.Z., S.H., J.C., J.Z., F.L., R.J., X.C., Y.L., X.Y.); Model Organism Division, E-institutes of Shanghai Universities, Shanghai Jiaotong University, Shanghai, PR China (P.Z., J.C., X.Y.); Institute of Vascular Medicine, Peking University Third Hospital and Key Laboratory of Molecular Cardiovascular..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fuyu","family":"Lin","sequence":"additional","affiliation":[{"name":"From the State Key Laboratory of Proteomics, Collaborative Innovation Center for Cardiovascular Disorders, Genetic Laboratory of Development and Diseases, Institute of Biotechnology, Beijing, PR China (P.Z., S.H., J.C., J.Z., F.L., R.J., X.C., Y.L., X.Y.); Model Organism Division, E-institutes of Shanghai Universities, Shanghai Jiaotong University, Shanghai, PR China (P.Z., J.C., X.Y.); Institute of Vascular Medicine, Peking University Third Hospital and Key Laboratory of Molecular 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