More than a decade ago people observed that angiogenic responses
could be inhibited by antioxidants or enhanced by exogenous reactive oxygen
molecules such as hydrogen peroxide. Accumulating experimental evidence
suggests that redox modulation of the function of thiol-containing proteins, such as
the protein tyrosine phosphatases, by reactive oxygen species has a pivotal role in
modulating intracellular signalings. NADPH oxidase is the sole enzymatic system
identified so far that has a dedicated function of generating reactive oxygen
molecules. It is not surprising that this enzyme has been implicated in modulating
angiogenic responses as shown in both in vitro and in vivo studies. NADPH
oxidase may exert proangiogenic effects by inducing growth factor release from
parenchymal cells and promoting angiogenic activities of vascular endothelial and
mural cells. Here we review the redox signaling mechanisms that are involved in
modulating angiogenesis, and different NADPH oxidase isoforms that may have a
role in such a process. Unlike growth factor receptor-mediated angiogenic signalings,
a feature of NADPH oxidase-mediated redox signaling is that, by inhibiting
protein tyrosine phosphatases, NADPH oxidase may represent an intracellular
signal amplifier for multiple receptor tyrosine kinase-mediated pathways involved
in angiogenesis. Pharmacological inhibitors of NADPH oxidase have been used to
suppress angiogenesis in different models. Encouragingly, drug targeting of
NADPH oxidase has been shown to be effective in reducing pathological
angiogenesis such as retinopathy. In summary, NADPH oxidase may be a new
drug target for antiangiogenic therapies, yet we are still facing great challenges in
achieving specific inhibition of different NADPH oxidase isoforms by drugs.
Keywords: Angiogenesis, NADPH oxidase, reactive oxygen species, redox signaling.
