Abstract 1884: Epigenetic Control of the Constitutive Overexpression of Smad2 in Aneurysms of the Human Ascending Aorta
Thoracic aortic aneurysm (TAA) development affects both smooth muscle cell (SMC) survival and vascular extracellular matrix (ECM) integrity. These features are present in all types of TAA:
monogenic diseases (Marfan syndrome),
aneurysms associated with bicuspid aortic valve (BAV) or
All types of TAA exhibit modifications of TGF-β1 biodisponibility corresponding with a localized increase in its retention within the ECM. Moreover, an activation of Smad2 (TGF-β mediator) is observed throughout the media. However, the relation between the genotypic variability and the cell phenotype relating to TGF-β signaling remains unexplained. We assessed the hypothesis that all types of TAA share a complex dysregulation of Smad signaling, independent of TGF-β1. Here, we investigated in detail TGF-β1 and Smad pathways in Marfan syndrome (FBN1: n=15, TGFBR2: n=3), BAV (n=15) or degenerative (n=19) aneurysms and control (n=10), using tissue extracts and cultured SMCs. We show an increase in Smad2 activation, corresponding to its phosphorylation, in all aneurysmal tissues, whatever the etiology. This Smad2 activation is specific (not involving Smad3 and non-Smad-TGF-β pathways), constitutive in SMCs, and independent of both TGF-β1 and TGF-β receptor functionality. An increased Smad2 expression (mRNA and protein) is observed in aneurysmal tissue extracts (relative Smad2 protein level; TAA: 1.8±1.2 vs control: 0.4±0.1, p<0.01) but also in cultured aneurysmal SMCs, in which the overexpression is maintained during several passages. Overexpression is limited to particular Smad2 variants and specific to SMCs (no perturbations occurred in aneurysmal adventitial fibroblasts). The cell-specificity and heritability of this overexpression strongly suggest the implication of epigenetic modifications on Smad2 promoter. We visualized, by ChIP, an increase in methylation and acetylation of the histones controlling Smad2 promoter activity, in aneurysmal tissue compared with control. In conclusion, we have demonstrated a dysregulation of Smad2 activation and expression in all forms of TAA. Smad2 overexpression is associated with epigenetic modifications of the histone code, in both genetic and non-genetic forms of TAA.