Mechanisms of atherogenesis: endothelial hypoxia proposed as the major initiator.

The major atherosclerosis risk factors hypertension, diabetes, hyperlipidemia and cigarette smoking are examined along with blood vessel anatomy, hemodynamics, histopathology and known experimental results. A common factor of blood vessel hypoxia, specifically endothelial and intimal hypoxia, is shown to exist. Arguments are presented suggesting endothelial hypoxia as the commonest initiating event for atherosclerosis. Cholesterol appears to be a secondary and opportunistic villain. Explanations are given for the lack of increased atherosclerosis risk in familial lipoprotein lipase deficiency (type I hyperlipoproteinemia) and for the increased incidence and severity of atherosclerosis in the human abdominal aorta in comparison with the thoracic aorta. It is suggested that effective prevention of atherosclerosis can be accomplished by lowering blood pressure and blood glucose, among others, even though these may be within acceptable normal limits. Suggestions are given for experiments to test the hypothesis of hypoxia being the major initiating factor in atherosclerosis.