New connections: The duality of ROS in angiogenesis

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Sci. Signal.  16 May 2017:
Vol. 10, Issue 479, eaan6438
DOI: 10.1126/scisignal.aan6438

Depending on the tissue and context, ROS can either stimulate or suppress blood vessel formation.

Defective angiogenesis contributes to the pathology of several diseases, such as impaired wound healing in diabetic individuals. Warren et al. discovered a mechanism underlying this phenomenon. Endothelial cells from a mouse model of diabetes had reduced cell surface abundance of VEGFR2, an angiogenesis-promoting receptor, which was associated with reduced responsiveness to its ligand, VEGF. Hyperglycemia generates reactive oxygen species (ROS), and the authors showed that ROS activated a family of kinases that phosphorylated VEGFR2 in an intracellular compartment, reducing the cell surface abundance of VEGFR2 and thus restricting angiogenic responses. Treating diabetic mice with an antioxidant restored cell surface VEGFR2 and enabled activation of VEGFR2 by VEGF. These results suggest that limiting ROS generation may boost angiogenic responses in diabetic individuals and that oxidative stress inhibits angiogenesis in general.

Defective angiogenesis also underlies preeclampsia, a condition in which the acute onset of high blood pressure in pregnant women impairs fetal growth and can result in maternal organ damage. Oxidative stress mediated by ROS has been proposed to inhibit angiogenesis in the placenta, which would be expected to increase the risk of preeclampsia; however, clinical trials have found antioxidants to be ineffective in preventing preeclampsia. Nezu et al. used a mouse model of preeclampsia in which the antioxidant system Nrf2 had been genetically or pharmacologically manipulated. Unexpectedly, genetic ablation of an inhibitor of Nrf2 or treatment with an activator of Nrf2 decreased placental angiogenesis, suppressed fetal growth, and worsened maternal survival. In contrast, deficiency in Nrf2 increased placental angiogenesis and improved fetal and maternal outcomes. Thus, ROS are necessary for the placental angiogenesis that reduces the risk of preeclampsia. In addition, these results suggest that ROS has a tissue- and context-specific effect on angiogenesis.

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