title: Early cell changes and TGFβ pathway alterations in the aortopathy associated with bicuspid aortic valve stenosis.
abstract: 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.
authors.affiliation: Department of Experimental Medicine, Second University of Naples, Naples, Italy.
authors.forename: Amalia
authors.initials: A
authors.lastname: Forte
authors.forename: Alessandro
authors.initials: A
authors.lastname: Della Corte
authors.forename: Mario
authors.initials: M
authors.lastname: Grossi
authors.forename: Ciro
authors.initials: C
authors.lastname: Bancone
authors.forename: Raffaela
authors.initials: R
authors.lastname: Provenzano
authors.forename: Mauro
authors.initials: M
authors.lastname: Finicelli
authors.forename: Marisa
authors.initials: M
authors.lastname: De Feo
authors.forename: Luca S
authors.initials: LS
authors.lastname: De Santo
authors.forename: Gianantonio
authors.initials: G
authors.lastname: Nappi
authors.forename: Maurizio
authors.initials: M
authors.lastname: Cotrufo
authors.forename: Umberto
authors.initials: U
authors.lastname: Galderisi
authors.forename: Marilena
authors.initials: M
authors.lastname: Cipollaro
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000704:Analysis of Variance; D000911:Antibodies, Monoclonal; D001021:Aortic Valve / Q000002:abnormalities / Q000473:pathology; D001024:Aortic Valve Stenosis / Q000378:metabolism* / Q000473:pathology*; D000082882:Bicuspid Aortic Valve Disease; D001837:Body Weights and Measures; D002454:Cell Differentiation / Q000502:physiology; D003598:Cytoskeletal Proteins / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D005260:Female; D005353:Fibronectins / Q000378:metabolism; D006349:Heart Valve Diseases / Q000473:pathology*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009124:Muscle Proteins / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000166:cytology* / Q000378:metabolism; D058628:Myofibroblasts / Q000502:physiology; D009687:Nuclear Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D018709:Statistics, Nonparametric; D015534:Trans-Activators / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D000099251:Myocardin
chemical_list: D000911:Antibodies, Monoclonal; D003598:Cytoskeletal Proteins; D017931:DNA Primers; D005353:Fibronectins; D009124:Muscle Proteins; D009687:Nuclear Proteins; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D000099251:Myocardin; C100762:SMTN protein, human