Yoshito Yamashiro1, Bui Quoc Thang2, Seung Jae Shin1,3, Caroline Antunes Lino4, Tomoyuki Nakamura5, Jungsil Kim6, Kaori Sugiyama7, Chiho Tokunaga2, Hiroaki Sakamoto2, Motoo Osaka2, Elaine C Davis8, Jessica E Wagenseil6, Yuji Hiramatsu2, Hiromi Yanagisawa1,9. 1. From the Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance (Y.Y., S.J.S., K.S., H.Y.). 2. Department of Cardiovascular Surgery (B.Q.T., C.T., H.S., M.O., Y.H.). 3. Graduate School of Life and Environmental Sciences (S.J.S.). 4. University of Tsukuba, Ibaraki, Japan; Department of Anatomy, Institute of Biomedical Sciences, University of Sao Paulo, Brazil (C.A.L.). 5. Department of Pharmacology, Kansai Medical University, Osaka, Japan (T.N.). 6. Department of Mechanical Engineering and Materials Science, Washington University, St. Louis, MO (J.K., J.E.W.). 7. PhD Program in Human Biology, School of Integrative and Global Majors (K.S.). 8. Department of Anatomy and Cell Biology, McGill University, Montreal, Quebec, Canada (E.C.D.). 9. Division of Biomedical Science, Faculty of Medicine (H.Y.).
Abstract
RATIONALE: Abnormal mechanosensing of smooth muscle cells (SMCs) resulting from the defective elastin-contractile units has been suggested to drive the formation of thoracic aortic aneurysms; however, the precise molecular mechanism has not been elucidated. OBJECTIVE: The aim of this study was to identify the crucial mediator(s) involved in abnormal mechanosensing and propagation of biochemical signals during the aneurysm formation and to establish a basis for a novel therapeutic strategy. METHODS AND RESULTS: We used a mouse model of postnatal ascending aortic aneurysms ( Fbln4SMKO; termed SMKO [SMC-specific knockout]), in which deletion of Fbln4 (fibulin-4) leads to disruption of the elastin-contractile units caused by a loss of elastic lamina-SMC connections. In this mouse, upregulation of Egr1 (early growth response 1) and angiotensin-converting enzyme leads to activation of Ang II (angiotensin II) signaling. Here, we showed that the matricellular protein, Thbs1 (thrombospondin-1), was highly upregulated in SMKO ascending aortas and in human thoracic aortic aneurysms. Thbs1 was induced by mechanical stretch and Ang II in SMCs, for which Egr1 was required, and reduction of Fbln4 sensitized the cells to these stimuli and led to higher expression of Egr1 and Thbs1. Deletion of Thbs1 in SMKO mice prevented the aneurysm formation in ≈80% of DKO (SMKO;Thbs1 knockout) animals and suppressed Ssh1 (slingshot-1) and cofilin dephosphorylation, leading to the formation of normal actin filaments. Furthermore, elastic lamina-SMC connections were restored in DKO aortas, and mechanical testing showed that structural and material properties of DKO aortas were markedly improved. CONCLUSIONS: Thbs1 is a critical component of mechanotransduction, as well as a modulator of elastic fiber organization. Maladaptive upregulation of Thbs1 results in disruption of elastin-contractile units and dysregulation of actin cytoskeletal remodeling, contributing to the development of ascending aortic aneurysms in vivo. Thbs1 may serve as a potential therapeutic target for treating thoracic aortic aneurysms.
RATIONALE: Abnormal mechanosensing of smooth muscle cells (SMCs) resulting from the defective elastin-contractile units has been suggested to drive the formation of thoracic aortic aneurysms; however, the precise molecular mechanism has not been elucidated. OBJECTIVE: The aim of this study was to identify the crucial mediator(s) involved in abnormal mechanosensing and propagation of biochemical signals during the aneurysm formation and to establish a basis for a novel therapeutic strategy. METHODS AND RESULTS: We used a mouse model of postnatal ascending aortic aneurysms ( Fbln4SMKO; termed SMKO [SMC-specific knockout]), in which deletion of Fbln4 (fibulin-4) leads to disruption of the elastin-contractile units caused by a loss of elastic lamina-SMC connections. In this mouse, upregulation of Egr1 (early growth response 1) and angiotensin-converting enzyme leads to activation of Ang II (angiotensin II) signaling. Here, we showed that the matricellular protein, Thbs1 (thrombospondin-1), was highly upregulated in SMKO ascending aortas and in humanthoracic aortic aneurysms. Thbs1 was induced by mechanical stretch and Ang II in SMCs, for which Egr1 was required, and reduction of Fbln4 sensitized the cells to these stimuli and led to higher expression of Egr1 and Thbs1. Deletion of Thbs1 in SMKO mice prevented the aneurysm formation in ≈80% of DKO (SMKO;Thbs1 knockout) animals and suppressed Ssh1 (slingshot-1) and cofilin dephosphorylation, leading to the formation of normal actin filaments. Furthermore, elastic lamina-SMC connections were restored in DKO aortas, and mechanical testing showed that structural and material properties of DKO aortas were markedly improved. CONCLUSIONS:Thbs1 is a critical component of mechanotransduction, as well as a modulator of elastic fiber organization. Maladaptive upregulation of Thbs1 results in disruption of elastin-contractile units and dysregulation of actin cytoskeletal remodeling, contributing to the development of ascending aortic aneurysms in vivo. Thbs1 may serve as a potential therapeutic target for treating thoracic aortic aneurysms.
Authors: Zhenjie Liu; Stephanie Morgan; Jun Ren; Qiwei Wang; Douglas S Annis; Deane F Mosher; Jing Zhang; Christine M Sorenson; Nader Sheibani; Bo Liu Journal: Circ Res Date: 2015-05-04 Impact factor: 17.367
Authors: Ronald V Lacro; Harry C Dietz; Lynn A Sleeper; Anji T Yetman; Timothy J Bradley; Steven D Colan; Gail D Pearson; E Seda Selamet Tierney; Jami C Levine; Andrew M Atz; D Woodrow Benson; Alan C Braverman; Shan Chen; Julie De Backer; Bruce D Gelb; Paul D Grossfeld; Gloria L Klein; Wyman W Lai; Aimee Liou; Bart L Loeys; Larry W Markham; Aaron K Olson; Stephen M Paridon; Victoria L Pemberton; Mary Ella Pierpont; Reed E Pyeritz; Elizabeth Radojewski; Mary J Roman; Angela M Sharkey; Mario P Stylianou; Stephanie Burns Wechsler; Luciana T Young; Lynn Mahony Journal: N Engl J Med Date: 2014-11-18 Impact factor: 91.245
Authors: Rute Moura; Marc Tjwa; Petra Vandervoort; Soetkin Van Kerckhoven; Paul Holvoet; Marc F Hoylaerts Journal: Circ Res Date: 2008-09-25 Impact factor: 17.367
Authors: S E Crawford; V Stellmach; J E Murphy-Ullrich; S M Ribeiro; J Lawler; R O Hynes; G P Boivin; N Bouck Journal: Cell Date: 1998-06-26 Impact factor: 41.582
Authors: Majed Dasouki; Dessislava Markova; Robert Garola; Takako Sasaki; Noe L Charbonneau; Lynn Y Sakai; Mon-Li Chu Journal: Am J Med Genet A Date: 2007-11-15 Impact factor: 2.802
Authors: Louis Saddic; Amanda Orosco; Dongchuan Guo; Dianna M Milewicz; Dana Troxlair; Richard Vander Heide; David Herrington; Yue Wang; Ali Azizzadeh; Sarah J Parker Journal: JVS Vasc Sci Date: 2022-01-22
Authors: Hisashi Sawada; Satoko Ohno-Urabe; Dien Ye; Michael K Franklin; Jessica J Moorleghen; Deborah A Howatt; Adam E Mullick; Alan Daugherty; Hong S Lu Journal: Arterioscler Thromb Vasc Biol Date: 2022-08-25 Impact factor: 10.514