This alternative pathway is especially important in oxidative environments, such as those associated with obesity, where endothelial dysfunction causes decreased eNOS activity due to factors like substrate (L-arginine) depletion, asymmetric dimethylarginine (ADMA) accumulation, and oxidative inactivation of tetrahydrobiopterin (BH4), a critical eNOS cofactor. Here, NOS3 is linked to endothelial dysfunction.