title: Syndromic and non-syndromic aneurysms of the human ascending aorta share activation of the Smad2 pathway.
abstract: Common features such as elastic fibre destruction, mucoid accumulation, and smooth muscle cell apoptosis are co-localized in aneurysms of the ascending aorta of various aetiologies. Recent experimental studies reported an activation of TGF-beta in aneurysms related to Marfan (and Loeys-Dietz) syndrome. Here we investigate TGF-beta signalling in normal and pathological human ascending aortic wall in syndromic and non-syndromic aneurysmal disease. Aneurysmal ascending aortic specimens, classified according to aetiology: syndromic MFS (n = 15, including two mutations in TGFBR2), associated with BAV (n = 15) or degenerative forms (n = 19), were examined. We show that the amounts of TGF-beta1 protein retained within and released by aneurysmal tissue were greater than for control aortic tissue, whatever the aetiology, contrasting with an unchanged TGF-beta1 mRNA level. The increase in stored TGF-beta1 was associated with enhanced LTBP-1 protein and mRNA levels. These dysregulations of the extracellular ligand are associated with higher phosphorylated Smad2 and Smad2 mRNA levels in the ascending aortic wall from all types of aneurysm. This activation correlated with the degree of elastic fibre fragmentation. Surprisingly, there was no consistent association between the nuclear location of pSmad2 and extracellular TGF-beta1 and LTBP-1 staining and between their respective mRNA expressions. In parallel, decorin was focally increased in aneurysmal media, whereas biglycan was globally decreased in aneurysmal aortas. In conclusion, this study highlights independent dysregulations of TGF-beta retention and Smad2 signalling in syndromic and non-syndromic aneurysms of the ascending aorta.
authors.affiliation: INSERM, U698, Paris, F-75018, France.
authors.forename: Delphine
authors.initials: D
authors.lastname: Gomez
authors.forename: Ayman
authors.initials: A
authors.lastname: Al Haj Zen
authors.forename: Luciano F
authors.initials: LF
authors.lastname: Borges
authors.forename: Monique
authors.initials: M
authors.lastname: Philippe
authors.forename: Paulo Sampaio
authors.initials: PS
authors.lastname: Gutierrez
authors.forename: Guillaume
authors.initials: G
authors.lastname: Jondeau
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Michel
authors.forename: Roger
authors.initials: R
authors.lastname: Vranckx
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001011:Aorta / Q000378:metabolism* / Q000473:pathology; D001014:Aortic Aneurysm / Q000150:complications / Q000235:genetics / Q000378:metabolism*; D015415:Biomarkers / Q000032:analysis; D016022:Case-Control Studies; D002454:Cell Differentiation; D015870:Gene Expression; D006801:Humans; D015151:Immunoblotting / Q000379:methods; D007150:Immunohistochemistry; D053779:Latent TGF-beta Binding Proteins / Q000032:analysis / Q000235:genetics; D008382:Marfan Syndrome / Q000150:complications / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000473:pathology; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D051899:Smad2 Protein / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D018709:Statistics, Nonparametric; D053773:Transforming Growth Factor beta1 / Q000032:analysis / Q000235:genetics / Q000378:metabolism*
chemical_list: D015415:Biomarkers; C509032:LTBP1 protein, human; D053779:Latent TGF-beta Binding Proteins; D012333:RNA, Messenger; C497782:SMAD2 protein, human; D051899:Smad2 Protein; D053773:Transforming Growth Factor beta1