Angiotensin II type 2 receptor overexpression activates the vascular kininsystem and causes vasodilation

Angiotensin II (Ang II) is a potent vasopressor peptide that interacts with 2 major receptor isoforms - AT1 and AT2. Although blood pressure is increa sed in AT2 knockout mice, the underlying mechanisms remain undefined becaus e of the low levels of expression of AT2 in the vasculature. Here we overex pressed AT2 in vascular smooth muscle (VSM) cells in transgenic (TG) mice. Aortic AT1 was not affected by overexpression of AT2. Chronic infusion of A ng II into AT2-TG mice completely abolished the AT1-mediated presser effect , which was blocked by inhibitors of bradykinin type 2 receptor (icatibant) and nitric oxide (NO) synthase (L-NAME). Aortic explants from TG mice show ed greatly increased cGMP production and diminished Ang II-induced vascular constriction. Removal of endothelium or treatment with icatibant and L-NAM E abolished these AT2-mediated effects. AT2 blocked the amiloride-sensitive Na+/H+ exchanger, promoting intracellular acidosis in VSM cells and activa ting kininogenases. The resulting enhancement of aortic kinin formation in TG mice was not affected by removal of endothelium. Our results suggest tha t AT2 in aortic VSM cells stimulates the production of bradykinin, which st imulates the NO/cGMP system in a paracrine manner to promote vasodilation. Selective stimulation of AT2 in the presence of AT1 antagonists is predicte d to have a beneficial clinical effect in controlling blood pressure.