Department of Experimental Medicine, Second University of Naples, Naples, Italy.
Clin Sci (Lond). 2013 Jan;124(2):97-108. doi: 10.1042/CS20120324.
Previous studies on BAV (bicuspid aortic valve)-related aortopathy, whose aetiology is still debated, have focused mainly on severe dilatations. In the present study, we aimed to detect earlier signs of aortopathy. Specimens were collected from the 'concavity' (lesser curvature) and the 'convexity' (greater curvature) of mildly dilated AAs (ascending aortas; diameter ≤4 cm) with stenotic TAV (tricuspid aortic valve) or BAV and from donor normal aortas. Specimens were submitted to morphometry, immunohistochemistry and differential gene-expression analysis, focusing on SMC (smooth muscle cell) phenotype, remodelling, MF (myofibroblast) differentiation and TGFβ (transforming growth factor β) pathway. Smoothelin and myocardin mRNAs decreased in all the samples from patients, with the exception of those from BAV convexity, where a change in orientation of smoothelin-positive SMCs and an increase of α-SMA (α-smooth muscle actin) mRNA occurred. Dilated aortas from BAV and TAV patients showed both shared and distinct alterations concerning the TGFβ pathway, including an increased TGFβ and TGFβR2 (TGFβ receptor 2) expression in both groups and a decreased TGFβR1 expression in BAV samples only. Despite a decrease of the mRNA coding for the ED-A (extra domain-A) isoform of FN (fibronectin) in the BAV convexity, the onset of the expression of the corresponding protein in the media was observed in dilated aortas, whereas the normal media from donors was negative for this isoform. This discrepancy could be related to modifications in the intima, normally expressing ED-A FN and showing an altered structure in mild aortic dilatations in comparison with donor aorta. Our results suggest that changes in SMC phenotype and, likely, MF differentiation, occur early in the aortopathy associated with valve stenosis. The defective expression of TGFβR1 in BAV might be a constitutive feature, while other changes we reported could be influenced by haemodynamics.
先前关于病因仍有争议的二叶式主动脉瓣（BAV）相关主动脉病变的研究主要集中在严重扩张上。在本研究中，我们旨在检测主动脉病变的早期迹象。采集了有狭窄三叶式主动脉瓣（TAV）或二叶式主动脉瓣和严重扩张的升主动脉（直径≤4 厘米）的“凹面”（曲率较小）和“凸面”（曲率较大）的标本。对标本进行形态计量学、免疫组织化学和差异基因表达分析，重点关注平滑肌细胞（SMC）表型、重塑、肌成纤维细胞（MF）分化和 TGFβ（转化生长因子β）途径。除了二叶式主动脉瓣凸面外，所有患者的标本中平滑肌蛋白和心肌蛋白 mRNA 均减少，而二叶式主动脉瓣凸面出现平滑肌蛋白阳性 SMC 方向改变和α-SMA（α-平滑肌肌动蛋白）mRNA 增加。二叶式主动脉瓣和 TAV 患者的扩张主动脉在 TGFβ 途径方面表现出既有共同又有独特的改变，包括两组 TGFβ 和 TGFβR2（TGFβ 受体 2）表达增加，而仅在二叶式主动脉瓣样本中 TGFβR1 表达减少。尽管二叶式主动脉瓣凸面纤维连接蛋白（FN）的 ED-A（额外结构域 A）同工型的 mRNA 减少，但在扩张主动脉中观察到该同工型蛋白在中膜的表达开始，而供体主动脉的正常中膜则为阴性。这种差异可能与内膜的改变有关，内膜通常表达 ED-A FN，与供体主动脉相比，在轻度主动脉扩张中结构改变。我们的结果表明，SMC 表型的改变，可能还有 MF 分化，在与瓣膜狭窄相关的主动脉病变中很早就发生了。二叶式主动脉瓣中 TGFβR1 的表达缺陷可能是一种固有特征，而我们报道的其他变化可能受血流动力学的影响。
