The interaction of nitric oxide, bradykinin, and the angiotensin II type 2 receptor: lessons learned from transgenic mice.

1013 Despite intensive study over the past few years, several aspects of the renin-angiotensin system remain poorly understood. Such is the case for the angiotensin II type 2 receptor (AT2), one of the two receptor subtypes that mediate the actions of angiotensin II. In fetal tissues, this receptor is expressed at high levels and appears to have a role in growth, differentiation, and maturation of cells in various organs, including the vasculature (1–4). As development progresses, the level of expression of the AT2 is downregulat-ed. In adult animals, in contrast to the wide distribution of angiotensin II type 1 receptor (AT1), AT2 is expressed at low levels and is restricted to the adre-nal gland, brain, ovary, uterus, kidney, and heart. Importantly, there appears to be upregulation of AT2 in pathological states such as salt depletion, heart failure, experimental cardiac hypertro-phy, myocardial infarction, and vascu-lar injury (3–8). Because of the low level of AT2 expression in normal tissues, there is substantial debate as to its role under normal circumstances. A growing body of research suggests that there is crosstalk between AT1 and AT2 in mediating the physiologic effects of angiotensin II. Based largely on pharmacological studies, stimulation of the AT2 seems to antagonize several of the effects caused by AT1 stimulation. Thus, AT1 stimulation activates the mitogen-activated protein kinases ERK1 and ERK2, whereas AT2 stimulation suppresses this pathway, perhaps by activating ERK phosphatase 1 (MKP-1) (4, 9, 10). AT1 stimulation promotes cellular growth and hyper-trophy, while the AT2 antagonizes them (3–6). AT1 stimulation facilitates angiogenesis, while the AT2 inhibits this process (11). AT1 activation induces vasoconstriction, while AT2 activation causes vasodilation (12). These cellular and organ-level effects appear to act in intact animal models as well. In cardiomyopathic hamsters, AT2 expression is upregulated in cardiac fibroblasts of the failing heart and appears to antagonize AT1–mediated progression of interstitial fibrosis and cardiac remodeling (6). Overexpression of AT2 in balloon-injured vascular smooth muscle cells attenuates neoin-timal formation (6). In a rat model of ischemic cardiomyopathy, the beneficial effects of AT1 blockade on cardiac remodeling and hemodynamics are inhibited by AT2 blockade (5). Recent work has suggested that some of the beneficial effects of AT2 stimulation may be meditated through the bradykinin/nitric oxide (NO) cascade (5, 13–15). Endothelial cells contain bradykinin type 2 receptors (B 2), which, when activated, potently stimulate production of NO. Although the effects of angiotensin II and NO seem to …