However, under disease-like conditions (e.g. high glucose, air pollution, and hypertension) that increase oxidative stress and an abundance of reactive oxygen species, levels of necessary cofactors such as tetrahydrobiopterin (BH4) can become insufficient for maintaining the redox reaction above, leading to eNOS ‘uncoupling’ (Figure 4).193–195 In this state, eNOS favours the production of superoxide (O2−) rather than NO. The gene discussed is NOS3; the disease is hypertensive disorder.