TY - JOUR
T1 - Role of thrombospondin-1 in mechanotransduction and development of thoracic aortic aneurysm in mouse and humans
AU - Yamashiro, Yoshito
AU - Thang, Bui Quoc
AU - Shin, Seung Jae
AU - Lino, Caroline Antunes
AU - Nakamura, Tomoyuki
AU - Kim, Jungsil
AU - Sugiyama, Kaori
AU - Tokunaga, Chiho
AU - Sakamoto, Hiroaki
AU - Osaka, Motoo
AU - Davis, Elaine C.
AU - Wagenseil, Jessica E.
AU - Hiramatsu, Yuji
AU - Yanagisawa, Hiromi
N1 - Funding Information:
differ from that of CTRL at any pressure, indicating the restoration of the material properties in DKO aortas. Taken together, prevention of aneurysm development was supported by normalization of material properties and improved quality of elastic fibers.
Funding Information:
We thank G. Urquhart, K. Matsumura, M. Masuda, J.V. Alves, and S. Sato for technical assistance, N.A. Abumrad for providing Cd36-null mice, P.A. Oldenborg for providing Cd47-null mice, and Y. Jinzenji and L.J. Ringuette for assistance with electron microscopy. We acknowledge technical support from the Facility for Electron Microscopy Research at McGill University and the Histology Core Laboratory at UT Southwestern Medical Center. We appreciate R. Ann Word for critical reading of the manuscript. This work was supported, in part, by grants from the Ministry of Education, Culture, Sports, Science and Technology KAKENHI (Grants-in-Aid for Scientific Research; grant No. JP 17H04289), The Naito Foundation, Astellas Foundation for Research on Metabolic Disorders to H. Yanagisawa and Grant-in Aid for Young Scientists (B; grant No. 15K20898), Japan Heart Foundation Research grant, the Inamori Foundation, Japan Foundation for Applied Enzymology and Takeda Science Foundation to Y. Yamashiro, National Institutes of Health (HL105314 and HL115560) to J.E. Wagenseil, and the National Sciences and Engineering Council of Canada (RGPIN 355710-13) to E.C. Davis. C.A. Lino was supported, in part, by the MEXT Inter-University Exchange Project.
Funding Information:
We thank G. Urquhart, K. Matsumura, M. Masuda, J.V. Alves, and S. Sato for technical assistance, N.A. Abumrad for providing Cd36-null mice, P.A. Oldenborg for providing Cd47-null mice, and Y. Jinzenji and L.J. Ringuette for assistance with electron microscopy. We acknowledge technical support from the Facility for Electron Microscopy Research at McGill University and the Histology Core Laboratory at UT Southwestern Medical Center. We appreciate R. Ann Word for critical reading of the manuscript.
Publisher Copyright:
© 2018 American Heart Association, Inc.
PY - 2018
Y1 - 2018
N2 - 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.
AB - 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.
KW - Angiotensin II
KW - Aortic aneurysm thoracic
KW - Elastic tissue
KW - Extracellular matrix
KW - Humans
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U2 - 10.1161/CIRCRESAHA.118.313105
DO - 10.1161/CIRCRESAHA.118.313105
M3 - Article
C2 - 30355232
AN - SCOPUS:85055607949
SN - 0009-7330
VL - 123
SP - 660
EP - 672
JO - Circulation research
JF - Circulation research
IS - 6
ER -