title: Spatiotemporal patterns of smooth muscle cell changes in ascending aortic dilatation with bicuspid and tricuspid aortic valve stenosis: focus on cell-matrix signaling.
abstract: OBJECTIVE
  The present study examined temporal and spatial patterns of extracellular matrix and smooth muscle cell changes in the ascending aorta with bicuspid and tricuspid aortic valve stenosis.
  
  
  METHODS
  Wall specimens were retrieved from both the greater and the lesser curvature ("convexity" and "concavity") of 14 nonaneurysmal and 12 aneurysmal aortas (aortic ratios 1.2 and 1.5, respectively) and from 3 heart donors (normal). Immunochemistry was performed for detection of apoptotic (terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling [TUNEL]-positive) and proliferating (Ki-67-positive) smooth muscle cells and for semiquantification of matrix proteins (collagens, fibronectin, tenascin, laminin). Co-immunoprecipitation assessed the extent of Bcl-2-modifying factor binding to Bcl-2, indicating a matrix-derived cytoskeleton-mediated proapoptotic signaling. Polymerase chain reaction allowed for quantification of messenger RNA expression for Bcl-2.
  
  
  RESULTS
  In both bicuspid and tricuspid aneurysms, fibrillar collagens were reduced, whereas fibronectin and tenascin were increased compared with those in normal conditions. These matrix alterations were already evident in bicuspid nonaneurysmal aortas at the convexity, with significant elevation of apoptotic indexes (P = .02 bicuspid vs normal; P = .48 tricuspid vs normal). Apoptotic indexes correlated with aortic dimensions only in tricuspid aortas (P = .01). No significant increase in Ki-67 was found. Higher levels of Bcl-2-modifying factor-Bcl-2 binding were found in bicuspid nonaneurysmal aorta versus tricuspid (P = .03) and normal aortas (P = .01). Bcl-2 messenger RNA expression was reduced in the bicuspid aorta versus normal (P = .08).
  
  
  CONCLUSIONS
  Smooth muscle cell apoptosis with bicuspid aortic valve stenosis occurred before overt aortic dilation, mainly at the convexity, where wall stress is expectedly higher. In this setting, a matrix-dependent proapoptotic signaling was evidenced by increased Bcl-2-modifying factor-Bcl-2 binding. Stress-dependent bicuspid aortic valve matrix changes may trigger early apoptosis by inducing cytoskeletal rearrangement.
authors.affiliation: Department of Cardiothoracic and Respiratory Sciences, Second University of Naples, V. Monaldi Hospital, Naples, Italy. aledellacorte@libero.it
authors.forename: Alessandro
authors.initials: A
authors.lastname: Della Corte
authors.forename: Cesare
authors.initials: C
authors.lastname: Quarto
authors.forename: Ciro
authors.initials: C
authors.lastname: Bancone
authors.forename: Clotilde
authors.initials: C
authors.lastname: Castaldo
authors.forename: Franca
authors.initials: F
authors.lastname: Di Meglio
authors.forename: Daria
authors.initials: D
authors.lastname: Nurzynska
authors.forename: Luca S
authors.initials: LS
authors.lastname: De Santo
authors.forename: Marisa
authors.initials: M
authors.lastname: De Feo
authors.forename: Michelangelo
authors.initials: M
authors.lastname: Scardone
authors.forename: Stefania
authors.initials: S
authors.lastname: Montagnani
authors.forename: Maurizio
authors.initials: M
authors.lastname: Cotrufo
mesh_terms: D000328:Adult; D000368:Aged; D001011:Aorta; D001014:Aortic Aneurysm / Q000150:complications / Q000503:physiopathology*; D001018:Aortic Diseases / Q000503:physiopathology; D001024:Aortic Valve Stenosis / Q000150:complications / Q000503:physiopathology*; D017209:Apoptosis; D004108:Dilatation, Pathologic / Q000503:physiopathology; D005109:Extracellular Matrix; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D032389:Myocytes, Smooth Muscle / Q000502:physiology*; D015398:Signal Transduction
chemical_list: D016326:Extracellular Matrix Proteins