Endothelial MMP-9 Drives the Inflammatory Response in Abdominal Aortic Aneurysm (AAA)

Abdominal aortic aneurysm (AAA) is a complex multi-factorial disease leading to life-threatening complications. Chronic inflammation and extracellular matrix degradation are the major pathological features of AAA. Vascular inflammation involves complex interaction among inflammatory cells (i.e. neutrophils, lymphocytes, monocytes, macrophages), endothelial cells (ECs), vascular smooth muscle cells (VSMCs), and extracellular matrix (ECM). Although vascular endothelium plays a key role in aneurysm disease, the molecular mechanisms underlying its involvement is only partially understood. In this study, we have characterized the role of matrix matrix metalloproteinase-9 (MMP-9) as potential trigger of the inflammatory response during the reciprocal interaction between ECs and VSMCs. Briefly, in biopsies of human AAA we found increased level of MMP-9, IL-6 and monocyte chemoattractant protein-1 (MCP-1), which correlated with a massive medial neo-angiogenesis. In particular, in vitro silencing of MMP-9 in ECs, using specific shRNA delivered by lentiviral vectors, inhibited TNF-alpha mediated activation of NF-kB. In addition, ECS void of MMP-9 failed to migrate in 3D matrix and affected VSMC behavior in terms of matrix remodeling. Overall our findings indicate that silencing of MMP-9 may represent a therapeutic target to restore vascular extracellular matrix remodeling.