Redox Signals that Regulate the Vascular Response to Injury
Bradford C. Berk
Center for Cardiovascular Research, University of Rochester, Rochester, NY, USA
Reactive oxygen species (ROS), generated by a variety of extracellular and intracellular mechanisms, are novel signal mediators that regulate signal transduction events. In this discussion, ROS will refer to H2O2, O2-, and OH-. Data suggest that, following vascular injury, ROS production is increased. These ROS activate signal events that are required for the repair process. Three key findings from our laboratories support the concept that oxidative stress is an important stimulus in the vessel wall for vascular repair, vascular smooth muscle cell (VSMC) growth, and vascular lesion formation. First, following oversized balloon inflation-induced porcine coronary artery injury, there is increased production of oxygen radicals (O2-, H2O2, and OH-) in the vessel wall for several weeks.1 Second, administration of several antioxidants including probucol, vitamins C and E, and L-cysteine decreases neointimal proliferation and/or promotes vessel remodeling in pig and rat injury models.1-3 Third, in vitro, we have shown that ROS stimulate VSMC growth and activate signal events typical of VSMC mitogens.4,5
A scheme for the mechanism by which oxidative stress is proposed in Figure 1. The initial vascular injury produced by balloon inflation rapidly increases the local concentration of ROS, which stimulate further generation of ROS by multiple mechanisms including xanthine oxidase, NADH oxidase, phospholipases, and mitochondrial electron transport dysfunction. In the setting of VSMC growth stimulation (by platelet and VSMC-derived mitogens) and cytokine stimulation (by leukocytes), there is amplification of ROS generating systems. These processes cause the cellular redox state to become more oxidized. This establishes a self-perpetuating increase in ROS production. Next, changes in cellular redox state stimulate growth-related signal transduction events. Until recently, VSMC growth was thought to be mediated largely by peptide growth factors. Published data from our laboratory show that ROS increase intracellular calcium, activate protein kinases, increase protooncogene expression, and stimulate DNA synthesis mitogens.4-6 However, the specific mechanisms by which the sustained oxidative stress present in the injured vessel stimulates VSMC growth remain undefined. Data presented indicate that redox sensitive signal pathways may be defined by specific activation of upstream mediators, which include phospholipases, small G proteins, and tyrosine kinases. Final effectors include serine-threonine kinases, such as the mitogen activated protein (MAP) kinases that activate specific transcription factors.