Reactive Oxygen Species Promote Vascular Smooth Muscle Cell Proliferation

Abstract

Do reactive oxygen species play a role in the pathogenesis of cardiovascular diseases? In 1992, Dr Berk and his group published an article that began to answer this question. During the following years, they performed a series of research projects that established the role of reactive oxygen species in vascular smooth muscle cell proliferation and cardiovascular diseases. It is now widely recognized that production of intracellular reactive oxygen species (ROS) is substantially involved in the pathogenesis of cardiovascular diseases, in part by promoting vascular smooth muscle cell (VSMC) proliferation. However, 20 years ago, it was elusive why VSMCs proliferate in response to arterial injury. Thus, Dr Berk et al hypothesized that ROS generated during arterial injury could be a common mechanism involved. Using xanthine/xanthine oxidase to generate ROS, they were able to demonstrate that ROS stimulate VSMC proliferation in vitro and that H2O2 was primarily responsible for xanthine/xanthine oxidase–induced VSMC DNA synthesis.1 This Circulation Research article was the first milestone article that directly demonstrated the role of ROS in VSMC proliferation, triggering the studies that followed targeting the role of ROS in the pathogenesis of cardiovascular diseases. Until now, this article has been referenced by more than 450 articles. Three years later, they further reported that both O2− and H2O2 stimulate VSMC growth but only O2− rapidly activates MAP kinase, suggesting that additional signal events are required for the mitogenic effects of H2O2.2 Based on these reports, it has been elucidated that the excess amount of ROS (oxidative stress) promotes VSMC proliferation and potentially develops cardiovascular diseases. In the subsequent 5 years, they focused on the interesting finding that ROS stimulates ERK1/2 in a biphasic manner in VSMCs. Finally, they demonstrated that one explanation …