IN-DEPTH ANALYSIS OF HUMAN VASCULAR SMOOTH MUSCLE CELLS FROM IDIOPATHIC THORACIC AORTIC ANEURYSM PATIENTS EVIDENCES THE MECHANISMS PREDISPOSING TO AORTIC DILATATION IN BICUSPID AORTIC VALVE

Background and Aims: To identify the hallmarks that difference the aortic dilatation associated to bicuspid (BAV) and tricuspid aortic valve (TAV) patients Methods: A total of 91 patients with idiopathic thoracic aortic aneurysm (TAA) or without aortic dilatation (control) were recruited and classified according to valve type as having BAV or TAV. To identify in tissue changes VSMCs were isolated from TAA aortas, and protein levels and protein coordinated behavior were differentially analyzed in BAV-TAA versus TAV-TAA by high throughput proteomics. To identify diagnostic markers, plasma quantification of TAA secreted proteins was performed compared to control patients for each valve type by ELISA and correlated with aortic diameter Results: VSMC contractile and proliferative phenotypes did not differ significantly between BAV and TAV patients. However, BAV-TAA patients exhibited a stress phenotype affecting protein homeostasis and featuring DNA damage and poor DNA repair, together with increased signal transduction mediated by G proteins. Vascular remodeling in BAV was reflected in diminished focal adhesions, weakened extracellular matrix interactions, and cell death, resulting in a defective arterial wall with poor adaptive capacity to external mechanical forces. Two individual diagnostic marker panels valve-associated were identified. Correlations with aortic diameter were found for C1QTNF5, LAMA2, and SPARC in BAV patients and for CP and FAP in TAV patients Conclusions: The molecular pathways here identified in the human aorta evidence differences in TAA of BAV or TAV patients that support differential therapeutic approaches