Early cell changes and TGF-beta pathway alterations in the aortopathy associated with bicuspid aortic valve stenosis.

""Previous studies on bicuspid aortic valve (BAV)-related aortopathy, whose etiology is still debated, focused mainly on severe dilatations. Here we aimed to detect earlier aortopathy signs. Specimens were collected from the "concavity" (lesser curvature) and the "convexity" (greater curvature) of mildly dilated ascending aortas (diameter ≤4 cm) with stenotic tricuspid aortic valve (TAV) or BAV and from donor normal aortas. Specimens were submitted to morphometry, immunohistochemistry and differential gene expression analysis, focusing on smooth muscle cell (SMC) phenotype, remodeling, myofibroblast differentiation and Transforming Growth Factor-b (TGF-b) 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 alpha-SM actin mRNA occurred. Dilated aortas from BAV and TAV patients showed both shared and distinct alterations concerning the TGF-b pathway, including an increased TGF-b and TGF-b-receptor-2 (TGFbR2) expression in both groups and a decreased TGFbR1 expression in BAV samples only. Despite a decrease of the mRNA coding for the extra domain-A isoform of fibronectin (ED-A FN) 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 to donor aorta. Our results suggest that changes in SMC phenotype and, likely, myofibroblast differentiation, occur early in the aortopathy associated with valve stenosis. The defective expression of TGFbR1 in BAV might be a constitutive feature, while other changes we reported could be influenced by hemodynamics.""