Redox signaling of angiogenesis.
Reactive oxygen species (ROS) play a crucial role in vascular angiogenesis. Both in vitro and in vivo studies indicate that angiogenic response in vascular tissue is triggered by ROS signaling in a highly coordinated manner. It appears that massive amounts of ROS produced during ischemia and reperfusion in the vascular tissue, especially in heart, cause significant injury to the cardiomyocyte and endothelial cells. However, during the reperfusion, the same ROS potentiates a repair process and triggers a signal transduction cascade leading to angiogenesis. Although several other factors are likely to be involved for such angiogenic response, ROS certainly plays a crucial role as evident from its direct role as mediator of angiogenesis and inhibition of angiogenesis with free radical scavengers and/or antioxidants. Angiogenesis is regulated by redox-sensing transcription factors such as nuclear factor-kappaB, and oxidants such as hydrogen peroxide and free radicals, such as nitric oxide may function as second messengers in this highly coordinated process. Furthermore, expression of many angiogenic genes including those for vascular endothelial growth factor, fibroblast growth factor, platelet-derived growth factor, and receptors such as Flt-1, Flk-1, Ang-1, and Ang-2 are likely to be regulated by redox signaling. It is tempting to speculate that the angiogenic response is under the autocrine and/or paracrine control of one or more cytokines, which in turn is redox-regulated. Through angiogenesis, ROS appear to pave the way of repairing the vascular tissues that have been damaged during ischemia and reperfusion.