Ascending aortic aneurysm (AscAA) development proceeds by multifactorial and chronic processes affecting both vascular extracellular matrix structure and integrity and smooth muscle cell (SMC) survival. These features are associated with all types of AscAA: i) genetic forms associated with mutations in FBN1, TGFBR1 or TGFBR2 (Marfan syndrome (MFS) and Loeys-Dietz syndrome (LDS)), ii) aneurysms associated with bicuspid aortic valve (BAV) or iii) degenerative forms. However, the relation between the genotypic variability and the unique aortic phenotype remains unexplained. The common matrix perturbations suggest similar cell dysfunction in both genetic and non-genetic AscAA. In this context, it has been recently proposed that TGF-β1 plays a predominant role in AscAA. Here we investigate TGF-β1 and its intracellular mediator Smad signaling pathway using tissue extracts and cultured SMCs from the media of genetic and non-genetic forms of AscAA. We show an increased activation of Smad2 (phosphorylated-Smad2) and an increased amount of TGF-β1 in AscAA. However, biochemical and histological studies demonstrated an enhancement of TGF-β1 retention within the extracellular matrix but not in its expression and activation, and thus highlight independent dysregulation of TGF-β1 retention and Smad2 signaling in genetic and non-genetic aneurysms. The constitutive Smad2 activation is independent of the extracellular TGF-β1 as well as of TGF-β receptor functionality. Aneurysms bearing TGFBR2 mutations, which induce loss of function, present constitutive Smad2 activation. Moreover, increased Smad2 expression is observed in tissue extracts but also in cultured SMC extracts, where the overexpression is surprisingly maintained during several passages, in AscAA. The study of adventitial fibroblasts shows that Smad2 perturbations are specific to SMCs from the media of aneurysmal aortic wall. A putative regulation of Smad2 expression by epigenetic mechanisms (histone acetylation and/or DNA methylation) is tested. Preliminary results show decreased Smad2 expression induced by deacetylase and methylase inhibitors in aneurysmal SMCs. In contrast, Smad2 expression, in control SMCs, is not affected by these treatments. The constitutive and tissuespecific activation of Smad2 and its maintained expression suggest an implication of epigenetic mechanisms in the development of genetic and non-genetic AscAA.