title: Disruption of TGF-β signaling in smooth muscle cell prevents elastase-induced abdominal aortic aneurysm.
abstract: Transforming growth factor-β (TGF-β) signaling has been significantly implicated in the pathogenesis of aneurysm, prominently the initiation and progression of abdominal aortic aneurysm (AAA). Vascular smooth muscle cell (SMC) is the principal resident cell in aortic wall and is essential for its structure and function. However, the role of TGF-β pathway in SMC for the formation of AAA remains unknown. Therefore, the goal of the present study was to investigate the effect of TGF-β pathway in SMC for AAA pathogenesis, by using a genetical smooth muscle-specific (SM-specific) TGF-β type II receptor (Tgfbr2) disruption animal model. Mice deficient in the expression of Tgfbr2 (MyhCre.Tgfbr2(f/f) and MyhCre.Tgfbr2(WT/f)) and their corresponding wild-type background mice (MyhCre.Tgfbr2(WT/WT)) underwent AAA induction by infrarenal peri-adventitial application of elastase. Fourteen days after elastase treatment, the aortas were analyzed and indicated that disruption of 1 or 2 alleles of Tgfbr2 in SMC provided markedly step-wise protection from AAA formation. And elastin degradation, medial SMC loss, macrophage infiltration, and matrix metalloproteinases (MMP) expression were all significantly reduced in Tgfbr2 deletion mice. Our study demonstrated, for the first time, that the TGF-β signaling pathway in SMC plays a critical role in AAA and disruption can prevent the aneurysm formation.
authors.affiliation: Department of Vascular Surgery, Peking University People's Hospital, Beijing, People's Republic of China.
authors.forename: Fu
authors.initials: F
authors.lastname: Gao
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire (CNRS UMR7104; INSERM U596; ULP, Collége de France) and Institut Clinique de la Souris, ILLKIRCH, Strasbourg, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Chambon
authors.affiliation: Department of Pharmacology, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Offermanns
authors.affiliation: Department of Surgery, Interdepartmental Program in Vascular Biology and Therapeutics, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: George
authors.initials: G
authors.lastname: Tellides
authors.affiliation: Department of Physiology and Pathophysiology, Basic Medical College of Peking University, Beijing, People's Republic of China.
authors.forename: Wei
authors.initials: W
authors.lastname: Kong
authors.affiliation: Department of Vascular Surgery, Peking University People's Hospital, Beijing, People's Republic of China. Electronic address: rmygxgwk@163.com.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Vascular Surgery, Peking University People's Hospital, Beijing, People's Republic of China.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
mesh_terms: D000818:Animals; D017544:Aortic Aneurysm, Abdominal / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D006579:Heterozygote; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D032389:Myocytes, Smooth Muscle / Q000378:metabolism* / Q000473:pathology; D010196:Pancreatic Elastase / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D010196:Pancreatic Elastase; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse
keywords: Aneurysm; Elastase; Smooth muscle cell; TGF-β