Role of Thrombospondin-1 in Mechanotransduction and Development of Thoracic Aortic Aneurysm in Mouse and Humans

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 iden...

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Bibliographic Details
Published in:Circulation research 2018-08, Vol.123 (6), p.660-672
Main Authors: Yamashiro, Yoshito, Thang, Bui Quoc, Shin, Seung Jae, Lino, Caroline Antunes, Nakamura, Tomoyuki, Kim, Jungsil, Sugiyama, Kaori, Tokunaga, Chiho, Sakamoto, Hiroaki, Osaka, Motoo, Davis, Elaine C, Wagenseil, Jessica E, Hiramatsu, Yuji, Yanagisawa, Hiromi
Format: Article
Language:English
Subjects:
Actin Cytoskeleton - metabolism
Actin Cytoskeleton - pathology
Aged
Aged, 80 and over
Animals
Aorta, Thoracic - metabolism
Aorta, Thoracic - pathology
Aortic Aneurysm, Thoracic - genetics
Aortic Aneurysm, Thoracic - metabolism
Aortic Aneurysm, Thoracic - pathology
Aortic Aneurysm, Thoracic - prevention & control
Cells, Cultured
Cofilin 2 - metabolism
Dilatation, Pathologic
Disease Models, Animal
Early Growth Response Protein 1 - metabolism
Elastic Tissue - metabolism
Elastic Tissue - pathology
Elastin - metabolism
Extracellular Matrix Proteins - deficiency
Extracellular Matrix Proteins - genetics
Female
Humans
Male
Mechanotransduction, Cellular
Mice, Knockout
Middle Aged
Muscle, Smooth, Vascular - metabolism
Muscle, Smooth, Vascular - pathology
Phosphoprotein Phosphatases - metabolism
Phosphorylation
Pressoreceptors - metabolism
Rats
Stress, Mechanical
Thrombospondin 1 - deficiency
Thrombospondin 1 - genetics
Thrombospondin 1 - metabolism
Vascular Remodeling
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Summary: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 (Fbln4; 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.
ISSN:0009-7330
1524-4571
DOI:10.1161/CIRCRESAHA.118.313105