Non-ischemic hypoxia of the arterial wall is a primary cause of atherosclerosis.

The response-to-injury hypothesis has been the dominant model of atherosclerosis for 20 years. However, it does not explain the experimental role of oxygen in atherogenesis, does not explain many of the clinical features of atherosclerosis, and has failed to provide useful countermeasures. I propose that arterial wall hypoxia results from risk factors for atherosclerosis. The primary mechanism is decreased oxygen delivery by a microcirculatory derangement resulting from impaired erythrocyte deformability. As in a healing wound, hypoxia causes growth factor release within the arterial media. Diffusion of these factors causes intimal proliferation and atheroma formation. This hypothesis implies that simple inexpensive oxygenation regimens might prevent the morbidity and mortality of atherosclerosis. Despite demonstrated effectiveness in experimental models, such treatments have not been extensively studied in clinical atherosclerosis because they conflict with the dominant model. This dogma needs to be re-examined.