Chronic changes in wall shear stress lead to vascular remodelling, characterized by increased vascular wall diameter and thickness, to restore wall shear stress values to baseline. Release of nitric oxide (NO) from endothelial cells exposed to excessive shear is a fundamental step in the remodelling process, and potentially triggers a cascade of events, including growth factor induction and matrix metalloproteinase (MMP) activation, that together contribute to restructuralisation of the vessel wall. MMPs, which are secreted as inactive zymogens (pro-MMPs), are rapidly cleaved and activated in in vivo models of chronic increased blood flow, and remain active until shear stress is normalized. Enhanced production of NO in high flow conditions, along with generation of reactive oxygen species through NADPH oxidase, combine to form peroxynitrite, which is important for MMP cleavage in the early phase of arterial remodelling. However, the later phase of this process implicates not only the activation of MMPs but also their ongoing synthesis. In this respect, we have uncovered a role for NF-kappaB as a key factor regulating the expression of MMP-9 and thus participating to the remodelling of vessels.