Rationale: The activation of the Smad2 signaling pathway is thought to play an important role in human aneurysmal diseases as described by an important body of research. We previously showed that constitutive Smad2 activation is associated with Smad2 mRNA overexpression in aneurysmal vascular smooth muscle cells (VSMCs) which is dependent on epigenetic regulation of the SMAD2 promoter involving histone modifications. However, the underlying molecular mechanisms controlling Smad2 overexpression are currently unknown. Objective: The aim of the present study is to understand the mechanisms regulating the constitutive Smad2 overexpression in VSMCs by the identification of the histone modifying enzymes, transcription factors and cofactors responsible for the Smad2 promoter activation in aneurysmal disease. Methods and Results: This study was performed on medial tissue extracts and primary cultures of VSMCs of human thoracic aneurysms (n=17) and normal thoracic aortas (n=10). Here, we demonstrate that the activation of the SMAD2 promoter is driven by the recruitment of a multi-partner complex including the transcription factor p53 and histone acetyltransferases (HATs). Remarkably, the transcription regulatory network of the SMAD2 promoter is dramatically altered in human aneurysmal VSMCs in vitro and in situ with a switch from Myc-dependent repression of SMAD2 in normal vessel to a p53-dependent activation of SMAD2 in aneurysms. Moreover, HATs p300/PCAF play a major role in the SMAD2 promoter activation by acting on histone acetylation, p53 recruitment and acetylation. Conclusions: These results provide evidence for a major role of p53 and the p300/PCAF complex in the Smad2 activation in human aneurysmal VSMCs.