Inserm Unit 698, Paris, University of Paris 7 (Denis Diderot), Paris, France.
Histopathology. 2010 Dec;57(6):917-32. doi: 10.1111/j.1365-2559.2010.03719.x.
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.
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.
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.
胸主动脉升部动脉瘤（TAA）的特征是主动脉中层弹性纤维断裂和囊性中层变性，伴有平滑肌细胞（SMC）逐渐减少。转化生长因子（TGF）-β/Smad2 信号通路参与了这一过程。由于细胞周纤维蛋白溶解系统的激活能够降解黏附蛋白、激活基质金属蛋白酶（MMP）、诱导 SMC 消失并增加 TGF-β的生物利用度，因此本研究旨在探讨 TAA 中的纤溶系统。
分析了 21 例对照和 19 例 TAA（三种不同病因）的升主动脉。免疫组织化学显示 t-PA、u-PA 和纤溶酶在 TAA 中蓄积，与残留的 SMC 相关。通过逆转录聚合酶链反应（RT-PCR）、免疫印迹和 TAA 提取物和 TAA 条件培养基的组织化学分析，证实了 t-PA 和 u-PA 的过表达。纤溶酶原存在于 SMC 表面和细胞质小泡内，但 TAA 中层中未检测到纤溶酶原 mRNA。TAA 条件培养基中检测到纤溶酶-抗纤溶酶复合物，纤维蛋白溶解系统的激活与纤维连接蛋白周转率的增加有关。免疫组织化学检测到 TAA 中纤维连接蛋白相关物质呈密集团块，与潜伏 TGF-β结合蛋白-1 共定位。
纤溶途径可能通过对细胞外基质的直接或间接影响以及对 TGF-β生物利用度的连续调节，在 TAA 进展中发挥关键作用。
