NOS3 and ischemia: Extensive ischemia at the distal of the grafted flap leads to excessive oxide aggregation; the levels of endogenous antioxidants, including heme oxygenase-1 (HO-1), endothelial nitric oxide synthase (eNOS), and superoxide dismutase (SOD), are insufficient to sustain the need for oxidative stress in the distal region of the grafted flap, ultimately leading to apoptosis [11].