Fibrinolytic activity is associated with presence of cystic medial degeneration in aneurysms of the ascending aorta

Fibrinolytic activity is associated with presence of cystic medial degeneration in aneurysms of the ascending aortaAims: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)-beta/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-beta, the aim was to investigate the plasminergic system in TAA.Methods and 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 immunohistochamically in dense clumps around SMCs and colocalized with latent TGF-beta 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-beta bioavailability.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Paris 7 University, FranceFrench National Research Agency (ANR)Societe Francaise de Cardiologie and Federation Francaise de CardiologieCoordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)European UnionUniv Paris 07, INSERM, U698, Paris, FranceUniversidade Federal de São Paulo, Ctr Electron Microscopy, São Paulo, BrazilCtr Reference Syndrome Marfan & Syndromes Apparen, Paris, FranceUniv São Paulo, Sch Med, Heart Inst InCor, Pathol Lab, São Paulo, BrazilUniversidade Federal de São Paulo, Ctr Electron Microscopy, São Paulo, BrazilEuropean Union: FP-7-Health-200647Web of Scienc