23
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: not found
      • Article: not found

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

      Read this article at

      ScienceOpenPublisherPMC
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          <div class="section"> <a class="named-anchor" id="S1"> <!-- named anchor --> </a> <h5 class="section-title" id="d6930514e261">Rationale</h5> <p id="P2">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 (TAAs); however, the precise molecular mechanism has not been elucidated. </p> </div><div class="section"> <a class="named-anchor" id="S2"> <!-- named anchor --> </a> <h5 class="section-title" id="d6930514e266">Objective</h5> <p id="P3">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. </p> </div><div class="section"> <a class="named-anchor" id="S3"> <!-- named anchor --> </a> <h5 class="section-title" id="d6930514e271">Methods and Results</h5> <p id="P4">We used a mouse model of postnatal ascending aortic aneurysms ( <i>Fbln4 <sup>SMKO</sup> </i>; termed <i>SMKO</i>), in which deletion of <i>Fbln4</i> leads to disruption of the elastin-contractile units caused by a loss of elastic lamina-SMC connections. In this mouse, upregulation of early growth response-1 (Egr1) and angiotensin converting enzyme leads to activation of angiotensin II signaling. Here we showed that the matricellular protein, thrombospondin-1 (Thbs1), was highly upregulated in <i>SMKO</i> ascending aortas and in human TAAs. Thbs1 was induced by mechanical stretch and Ang II in SMCs, for which Egr1 was required, and reduction of <i>Fbln4</i> sensitized the cells to these stimuli and led to higher expression of Egr1 and Thbs1. Deletion of <i>Thbs1</i> in <i>SMKO</i> mice prevented the aneurysm formation in approximately 80% of <i>SMKO; Thbs1 <sup>−/−</sup> </i> (termed <i>DKO</i>) animals and suppressed slingshot-1 and cofilin de-phosphorylation, leading to the formation of normal actin filaments. Furthermore, elastic lamina-SMC connections were restored in <i>DKO</i> aortas and mechanical testing showed that structural and material properties of <i>DKO</i> aortas were markedly improved. </p> </div><div class="section"> <a class="named-anchor" id="S4"> <!-- named anchor --> </a> <h5 class="section-title" id="d6930514e316">Conclusions</h5> <p id="P5">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 TAAs. </p> </div>

          Related collections

          Most cited references46

          • Record: found
          • Abstract: found
          • Article: not found

          Atenolol versus losartan in children and young adults with Marfan's syndrome.

          Aortic-root dissection is the leading cause of death in Marfan's syndrome. Studies suggest that with regard to slowing aortic-root enlargement, losartan may be more effective than beta-blockers, the current standard therapy in most centers.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Lessons on the pathogenesis of aneurysm from heritable conditions.

            Aortic aneurysm is common, accounting for 1-2% of all deaths in industrialized countries. Early theories of the causes of human aneurysm mostly focused on inherited or acquired defects in components of the extracellular matrix in the aorta. Although several mutations in the genes encoding extracellular matrix proteins have been recognized, more recent discoveries have shown important perturbations in cytokine signalling cascades and intracellular components of the smooth muscle contractile apparatus. The modelling of single-gene heritable aneurysm disorders in mice has shown unexpected involvement of the transforming growth factor-β cytokine pathway in aortic aneurysm, highlighting the potential for new therapeutic strategies.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Heterozygous TGFBR2 mutations in Marfan syndrome.

              Marfan syndrome is an extracellular matrix disorder with cardinal manifestations in the eye, skeleton and cardiovascular systems associated with defects in the gene encoding fibrillin (FBN1) at 15q21.1 (ref. 1). A second type of the disorder (Marfan syndrome type 2; OMIM 154705) is associated with a second locus, MFS2, at 3p25-p24.2 in a large French family (family MS1). Identification of a 3p24.1 chromosomal breakpoint disrupting the gene encoding TGF-beta receptor 2 (TGFBR2) in a Japanese individual with Marfan syndrome led us to consider TGFBR2 as the gene underlying association with Marfan syndrome at the MSF2 locus. The mutation 1524G-->A in TGFBR2 (causing the synonymous amino acid substitution Q508Q) resulted in abnormal splicing and segregated with MFS2 in family MS1. We identified three other missense mutations in four unrelated probands, which led to loss of function of TGF-beta signaling activity on extracellular matrix formation. These results show that heterozygous mutations in TGFBR2, a putative tumor-suppressor gene implicated in several malignancies, are also associated with inherited connective-tissue disorders.
                Bookmark

                Author and article information

                Journal
                Circulation Research
                Circ Res
                Ovid Technologies (Wolters Kluwer Health)
                0009-7330
                1524-4571
                August 31 2018
                August 31 2018
                : 123
                : 6
                : 660-672
                Affiliations
                [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.)
                Article
                10.1161/CIRCRESAHA.118.313105
                6211815
                30355232
                fdcfe365-7041-4057-8a7d-2ac52c291b47
                © 2018
                History

                Comments

                Comment on this article