title: Fibrinolytic activity is associated with presence of cystic medial degeneration in aneurysms of the ascending aorta.
abstract: OBJECTIVE
  Thoracic ascending aortic aneurysms (TAA) are characterized by elastic fibre breakdown and cystic medial degeneration within the aortic media, associated with progressive smooth muscle cell (SMC) rarefaction. The transforming growth factor (TGF)-β/Smad2 signalling pathway is involved in this process. Because the pericellular fibrinolytic system activation is able to degrade adhesive proteins, activate matrix metalloproteinase (MMP), induce SMC disappearance and increase the bioavailability of TGF-β, the aim was to investigate the plasminergic system in TAA.
  
  
  RESULTS
  Ascending aortas [21 controls and 19 TAAs (of three different aetiologies)] were analysed. Immunohistochemistry showed accumulation of t-PA, u-PA and plasmin in TAAs, associated with residual SMCs. Overexpression of t-PA and u-PA was confirmed by reverse transcription-polymerase chain reaction (RT-PCR), immunoblotting and zymography on TAA extracts and culture medium conditioned by TAA. Plasminogen was present on the SMC surface and inside cytoplasmic vesicles, but plasminogen mRNA was undetectable in the TAA medial layer. Plasmin-antiplasmin complexes were detected in TAA-conditioned medium and activation of the fibrinolytic system was associated with increased fibronectin turnover. Fibronectin-related material was detected immunohistochemically in dense clumps around SMCs and colocalized with latent TGF-β binding protein-1.
  
  
  CONCLUSIONS
  The fibrinolytic pathway could play a critical role in TAA progression, via direct or indirect impact on ECM and consecutive modulation of TGF-β bioavailability.
authors.affiliation: Inserm Unit 698, Paris, University of Paris 7 (Denis Diderot), Paris, France.
authors.forename: Luciano F
authors.initials: LF
authors.lastname: Borges
authors.forename: Delphine
authors.initials: D
authors.lastname: Gomez
authors.forename: Mercedes
authors.initials: M
authors.lastname: Quintana
authors.forename: Ziad
authors.initials: Z
authors.lastname: Touat
authors.forename: Guillaume
authors.initials: G
authors.lastname: Jondeau
authors.forename: Anne
authors.initials: A
authors.lastname: Leclercq
authors.forename: Olivier
authors.initials: O
authors.lastname: Meilhac
authors.forename: Martine
authors.initials: M
authors.lastname: Jandrot-Perrus
authors.forename: Paulo S
authors.initials: PS
authors.lastname: Gutierrez
authors.forename: Edna
authors.initials: E
authors.lastname: Freymuller
authors.forename: Roger
authors.initials: R
authors.lastname: Vranckx
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Michel
mesh_terms: D000328:Adult; D000368:Aged; D001011:Aorta / Q000378:metabolism*; D017545:Aortic Aneurysm, Thoracic / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D051899:Smad2 Protein / Q000235:genetics / Q000378:metabolism; D010959:Tissue Plasminogen Activator / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics / Q000378:metabolism*
chemical_list: D012333:RNA, Messenger; C497782:SMAD2 protein, human; D051899:Smad2 Protein; D016212:Transforming Growth Factor beta; D010959:Tissue Plasminogen Activator; D014568:Urokinase-Type Plasminogen Activator