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Angiotensin II (Ang II) signaling is mediated by two receptor subtypes, type 1 (AT_1) and type 2 (AT_2). The activation of AT_1 receptors is responsible for the development of Ang II-dependent hypertension, whereas the activation of AT_2 receptor is thought to play a counter-regulatory protective role in the regulation of blood pressure that opposes the AT_1 receptor-mediated vasoconstriction. However, the precise mechanisms by which increased numbers of AT_2 receptors counterbalance the AT_1-mediated actions of Ang II are unknown. We have demonstrated that the abdominal aortic banding in mice and rats and the 2-kidney, 1-clip Goldblatt model of hypertension in mice induces up-regulation of AT_2 receptors in the pressure-overloaded thoracic aorta. In these hypertensive animals, the AT_1-receptor antagonists but not calcium antagonist abolish up-regulation of the aortic AT_2 receptor as well as blood pressure elevation, suggesting that the pressure-overload up-regulates the aortic AT_2 receptor by Ang II via the activation of AT_1 receptor. Ang II binding to up-regulated AT_2 receptors induces vasodilation in these aortas through bradykinin B_2-receptor-mediated phosphorylation of endothelial nitric oxide synthase (eNOS) at Ser^<633> and Ser^<1177> via a protein kinase A-dependent signaling pathway, resulting in sustained production of nitric oxide. These studies provide evidence that the vascular AT_2 receptor is up-regulated in the course of hypertension through the activation of AT_1 receptor, thereby activating a vasodilatory pathway in vessels through the AT_2 receptor via the bradykinin/nitric oxide/cGMP. This issue is important because the antihypertensive effect of AT_1-receptor blockers is, at least in part, dependent on AT_2-receptor activation.
