Tissue angiotensin and pathobiology of vascular disease - A unifying hypothesis

There is increasing evidence that direct pathobiological events in the vess el wall play an important role in vascular disease. An important mechanism involves the perturbation of the homeostatic balance between NO and reactiv e oxygen species. Increased reactive oxygen species can inactivate NO and p roduce peroxynitrite. Angiotensin II is a potent mediator of oxidative stre ss and stimulates the release of cytokines and the expression of leukocyte adhesion molecules that mediate vessel wall inflammation. Inflammatory cell s release enzymes (including ACE) that generate angiotensin II. Thus, a loc al positive-feedback mechanism could be established in the vessel wall for oxidative stress, inflammation, and endothelial dysfunction. Angiotensin II also acts as a direct growth factor for vascular smooth muscle cells and c an stimulate the local production of metalloproteinases and plasminogen act ivator inhibitor. Taken together, angiotensin II can promote vasoconstricti on, inflammation, thrombosis, and vascular remodeling. In this article, we propose a model that unifies the interrelationship among cardiovascular ris k factors, angiotensin II, and the pathobiological mechanisms contributing to cardiovascular disease. This model may also explain the beneficial effec ts of ACE inhibitors on cardiovascular events beyond blood pressure reducti on.