title: Overexpression of transforming growth factor-beta is associated with increased hyaluronan content and impairment of repair in Marfan syndrome aortic aneurysm.
abstract: BACKGROUND
  Marfan syndrome (MFS), a condition caused by fibrillin-1 gene mutation is associated with aortic aneurysm that shows elastic lamellae disruption, accumulation of glycosaminoglycans, and vascular smooth muscle cell (VSMC) apoptosis with minimal inflammatory response. We examined aneurysm tissue and cultured cells for expression of transforming growth factor-beta1 to -beta3 (TGFbeta1 to 3), hyaluronan content, apoptosis, markers of cell migration, and infiltration of vascular progenitor cells (CD34).
  
  
  RESULTS
  MFS aortic aneurysm (6 males, 5 females; age 8 to 78 years) and normal aorta (5 males, 3 females; age 22 to 56 years) were used. Immunohistochemistry showed increased expression of TGFbeta1 to 3, hyaluronan, and CD34-positive microcapillaries in MFS aneurysm compared with control. There was increased expression of TGFbeta1 to 3 and hyaluronan in MFS cultured VSMCs, adventitial fibroblasts (AF), and skin fibroblasts (SF). Apoptosis was increased in MFS (VSMC: mean cell loss in MFS 29%, n of subjects=5, versus control 8%, n=3, P<0.05; AF: 28%, n=5 versus 7%, n=5, P<0.05; SF: 29%, n=3 versus 4%, n=3, not significant). In MFS, there was a 2-fold increase in adventitial microcapillaries containing CD34-positive cells compared with control tissue. Scratch wound assay showed absence of CD44, MT1-MMP, and beta-3 integrin at the leading edge of migration in MFS indicating altered directional migration. Western blot showed increased expression of TGFbeta1 to 3 in MFS but no change in expression of CD44, MT1-MMP, or beta-3 integrin compared with controls.
  
  
  CONCLUSIONS
  There was overexpression of TGF-beta in MFS associated with altered hyaluronan synthesis, increased apoptosis, impaired progenitor cell recruitment, and abnormal directional migration. These factors limit tissue repair and are likely to contribute to aneurysm development.
authors.affiliation: Department of Medicine, The University of Queensland, Prince Charles Hospital, Brisbane 4032, Australia.
authors.forename: Maria
authors.initials: M
authors.lastname: Nataatmadja
authors.forename: Jennifer
authors.initials: J
authors.lastname: West
authors.forename: Malcolm
authors.initials: M
authors.lastname: West
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000784:Aortic Dissection / Q000209:etiology / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D001011:Aorta / Q000378:metabolism; D001014:Aortic Aneurysm / Q000209:etiology / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D017209:Apoptosis; D019917:Blood Vessel Prosthesis Implantation; D002478:Cells, Cultured / Q000378:metabolism; D002648:Child; D017558:Elective Surgical Procedures; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D018960:Hyaluronan Receptors / Q000096:biosynthesis / Q000235:genetics; D006820:Hyaluronic Acid / Q000032:analysis*; D039661:Integrin beta3 / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D008382:Marfan Syndrome / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D020782:Matrix Metalloproteinases / Q000096:biosynthesis / Q000235:genetics; D053504:Matrix Metalloproteinases, Membrane-Associated; D008875:Middle Aged; D032342:Muscle Cells / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000096:biosynthesis* / Q000235:genetics; D053773:Transforming Growth Factor beta1; D053781:Transforming Growth Factor beta2; D053782:Transforming Growth Factor beta3
chemical_list: C497483:CD44 protein, human; D018960:Hyaluronan Receptors; D039661:Integrin beta3; C508960:TGFB1 protein, human; C509041:TGFB2 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D053781:Transforming Growth Factor beta2; D053782:Transforming Growth Factor beta3; D006820:Hyaluronic Acid; D020782:Matrix Metalloproteinases; D053504:Matrix Metalloproteinases, Membrane-Associated