Angiotensin Type 2 Receptor–Mediated Phosphorylation of eNOS in the Aortas of Mice With 2-Kidney, 1-Clip Hypertension

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Abstract
To evaluate the role of vascular angiotensin II (Ang II) type 2 (AT 2 ) receptor in renovascular hypertension, we investigated expressions of AT 2 receptor and endothelial nitric oxide synthase (eNOS) in thoracic aortas of mice with 2-kidney, 1-clip (2K1C) hypertension. The mRNA levels of AT 2 receptor in aortas, but not those of AT 1 and bradykinin B 2 receptors, increased 14 days but not 42 days after clipping. The contractile response to Ang II (>0.1 μmol/L) was attenuated in aortic rings excised 14 days after clipping and was restored to that of rings from sham mice by antagonists of AT 2 receptor (PD123319) and B 2 receptor (icatibant). The aortic levels of total eNOS, phosphorylated eNOS at Ser 1177 (p-eNOS), total Akt, and phosphorylated Akt at Ser 473 (p-Akt) were increased in 2K1C mice on day 14, whereas only eNOS levels were increased on day 42. The aortic cGMP levels were ≈20-fold greater in 2K1C mice on day 14 compared with sham mice. Administration of nicardipine for 4 days before the excision of aortas 14 days after clipping not only reduced blood pressure but also decreased the aortic levels of eNOS, p-eNOS, Akt, p-Akt, and cGMP to sham levels, whereas the administration of PD123319 or icatibant to 2K1C mice decreased p-eNOS and cGMP to sham levels without affecting blood pressure and the levels of eNOS, Akt and p-Akt. These results suggest that vascular NO production is enhanced by increased eNOS phosphorylation via the activation of AT 2 receptors in the course of 2K1C hypertension.