Role of oxidant stress in vascular proteolysis

Abstract

Proteolytic degradation of the matrix scaffold is a necessary component of tissue remodeling. We have proposed that specialized enzymes, called matrix metalloproteinases (MMPs), allow vascular wall remodeling in response to a variety of stimuli, but may ultimately weaken it, bringing about the destabilization and failure responsible for acute cardiovascular events. We are currently briefly reviewing the main evidence we have obtained regarding the key role of oxidative stress in MMP-driven remodeling. An essential finding was that reactive oxygen species (ROS), produced by inflammatory and vascular cells, could trigger activation of latent MMPs, thus leading to vascular matrix degradation. For instance, we showed that lipid-laden macrophages, a major source of both MMPs and ROS, are associated with increased proteolytic activity and drive expansive remodeling, which may explain their association with unstable human atherosclerotic plaques. Of note, vascular cells can also become a source of ROS. We found that active vascular remodeling was characterized by oxidant stress, MMP induction/activation, and matrix degradation. Conversely, we recently demonstrated that introduction of oxidative stress drives arterial lesion progression and angiogenesis. Thus, we propose that the therapeutic decrease of vascular oxidant stress may be used to control vascular remodeling and to increase the stability of atherosclerotic plaques.