In the nascent stages of atherosclerosis, non-hypoxic stimuli such as angiotensin II, TNF-α, or mildly oxidized low-density lipoprotein may assume paramount significance in eliciting the activation of HIF in ECs.90 Conversely, during the intermediate and advanced stages of atherosclerosis, hypoxic stimulation, through the activation of HIF-1α, confers upon ECs the ability to adapt to diminished metabolic requisites in a low-oxygen milieu.101 HIF-1α instigates profound transformations in ECs via three principal ways: VEGF, nitric oxide (NO), and ROS. The gene discussed is TNF; the disease is atherosclerosis.