Gomez Delphine, Al Haj Zen Ayman, Borges Luciano F, Philippe Monique, Gutierrez Paulo Sampaio, Jondeau Guillaume, Michel Jean-Baptiste, Vranckx Roger
INSERM, U698, Paris, F-75018, France.
J Pathol. 2009 May;218(1):131-42. doi: 10.1002/path.2516.
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.
诸如弹性纤维破坏、黏液样积聚和平滑肌细胞凋亡等常见特征在各种病因的升主动脉瘤中共同定位。最近的实验研究报道了与马凡（和洛伊迪茨）综合征相关的动脉瘤中转化生长因子-β（TGF-β）的激活。在此，我们研究综合征性和非综合征性动脉瘤疾病中正常和病理性人类升主动脉壁中的TGF-β信号传导。对根据病因分类的升主动脉瘤标本进行了检查：综合征性马凡综合征（MFS，n = 15，包括TGFBR2中的两个突变）、合并二叶式主动脉瓣（BAV，n = 15）或退行性病变（n = 19）。我们发现，无论病因如何，动脉瘤组织中保留和释放的TGF-β1蛋白量均高于对照主动脉组织，这与TGF-β1 mRNA水平未变形成对比。储存的TGF-β1增加与LTBP-1蛋白和mRNA水平升高相关。细胞外配体的这些失调与所有类型动脉瘤的升主动脉壁中磷酸化Smad2和Smad2 mRNA水平升高有关。这种激活与弹性纤维断裂程度相关。令人惊讶的是，pSmad2的核定位与细胞外TGF-β1和LTBP-1染色及其各自的mRNA表达之间没有一致的关联。同时，核心蛋白聚糖在动脉瘤中层局部增加，而双糖链蛋白聚糖在动脉瘤主动脉中整体减少。总之，本研究强调了升主动脉综合征性和非综合征性动脉瘤中TGF-β保留和Smad2信号传导的独立失调。
