Tissue Angiotensin and Pathobiology of Vascular Disease

Abstract

Abstract-There is increasing evidence that direct pathobiological events in the vessel wall play an important role in vascular disease. An important mechanism involves the perturbation of the homeostatic balance between NO and reactive oxygen species. Increased reactive oxygen species can inactivate NO and produce peroxynitrite. Angiotensin II is a potent mediator of oxidative stress and stimulates the release of cytokines and the expression of leukocyte adhesion molecules that mediate vessel wall inflammation. Inflammatory cells release enzymes (including ACE) that generate angiotensin II. Thus, a local 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 can stimulate the local production of metalloproteinases and plasminogen activator inhibitor. Revolutions, 1970 S ince its discovery a century ago, the role of the renin-angiotensin system as an endocrine system involved in blood pressure and fluid electrolyte regulation has been well established. 1 Disorders of this system contribute importantly to the pathophysiology of hypertension, renal disease, and congestive heart failure. The recent discoveries of the tissue actions of angiotensin II (Ang II) have revolutionized our thinking of the role of this peptide in cardiovascular disease. Evidence indicates that Ang II is more than a hormone that exerts hemodynamic and renal actions but that it is also a local, biologically active mediator that has direct effects on endothelial and smooth muscle cells. 2 It plays a key role in the initiation and amplification of pathobiological events that lead to vascular disease. Indeed, recent clinical trials of ACE inhibitors have consistently documented the salutary effects of this class of agents in treating and preventing cardiovascular disease, with impressive reductions in coronary and cerebral vascular events despite a modest effect on blood pressure lowering. [3][4][5] These data suggest that ACE inhibitors may also exert direct actions on the blood vessel beyond their hemodynamic effects. The present article reviews the evidence for the direct tissue actions of Ang II, the cellular signaling pathways, and the interactions of Ang II with other local mediators. It is hypothesized that these tissue effects are important in the process of vascular disease and may mediate the additional nonhemodynamic actions of ACE inhibitors in treating cardiovascular conditions, such as coronary artery disease. Endothelium, Oxidative Stress, and Vascular DiseaseTo understand the effect of Ang II on vascular pathobiology, we must first examine the role of the endothelium. Ang II is synthesized by and has a key action on the endothelium: it exerts direct influence on endothelial function. The endothelium is well recognized as having a pivotal role in maintaining normal vascular function and structure. 6 The endothelium presents a thromboresistant surface to blood and f...

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