Angiotensin Type 2 Receptor-Dependent Vasodilation

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.