Together, these findings implicate NADPH oxidase in ROS generation, STAT3 activation, VEGF expression, and intravitreous neovascularization in ROP. Consistent with these data, in-depth investigations during the past decade have further delineated which NADPH oxidase isoforms contribute to the regulation of VEGF expression, endothelial function, and angiogenesis. The NADPH oxidase family consists of the phagocyte NADPH oxidase (Nox 2/gp91phox [phox is short for phagocytic oxidase]) and 6 homologue members identified in nonphagocytes (Nox 1, Nox 3, Nox 4, Nox 5, Duox1, and Duox2). In the vascular system, Nox 1, Nox 2, Nox 4, and Nox 5 are expressed, but Nox 4 has the highest expression level in human retinal,36 umbilical,37 and aorta endothelial cells.38 Unlike the other Nox family members, the activity of Nox 4 does not require the cytosolic subunits P47phox, P67phox, and Rac139 but does require P22phox, which colocalizes with Nox 4 in the plasma membrane. Another important feature of Nox 4 is that it generates hydrogen peroxide instead of superoxide; therefore, it does not produce damaging peroxynitrite in the presence of nitric oxide. Nox 4 seems to have a role in hypoxia-inducible factor 1α (HIF1α) stabilization and in VEGF upregulation.36 In addition, Nox 4 was implicated in STAT3-mediated VEGF expression in endothelial cells36 and is required for endothelial cell proliferation and migration.40 These results indicate a potential role of NADPH oxidase4 in hypoxia-elicited proangiogenic responses of endothelial cells.41 The evidence of its role in apoptosis is conflicting.42,43 Nevertheless, how Nox is implicated in the pathogenesis of avascular retina and intravitreous neovascularization in ROP is of great interest and should be investigated in the future.