Effect of endothelial-specific nox2 overexpression on endothelial function and blood pressure

Abstract

NADPH oxidases are major sources of reactive oxygen species (ROS) involved in several vascular diseases, but the cell-specific roles of different Nox isoforms in vivo remain poorly defined. To address this question, we generated mice with endothelial-targeted overexpression of Nox2 oxidase using a tie2 promoter construct. Transgenic mice (TG) expressed increased Nox2 mRNA in endothelial-rich tissues, with 2.6-fold greater Nox2 protein in lung compared to wild-type littermates (WT). No difference in aortic expression of p22, Nox4 or eNOS mRNAwas detected in TG vs. WT. Basal NADPH oxidase activity in aortic tissue homogenates was similar in TG and WT. Endothelial-dependent relaxation to acetylcholine (Ach) in aortic rings was also similar in WTand TG (Emax: 87.9±1.8% in WT vs. 94.0±2.1% in TG). Acute ex vivo exposure to Angiotensin II (AngII) (100 nM, 30 min) increased aortic NADPH oxidase activity by 50% in TG vs. 25% in WT. In line with this, Ach-induced relaxation was more impaired in TG than WTafter ex vivo exposure to AngII (LogEC50 for the Ach response after AngII was −7.19±0.04 M in TG; p<0.05 vs. −7.37±0.08 M in WT). Basal blood pressure by tail-cuff plethysmography was 100.0±2.3 mmHg in WT vs. 95.1±1.7 mmHg in TG; p=NS. Blood pressure remained similar in the two groups after infusion of 0.3 mg/kg/day AngII for 2 weeks (WT 92.2±2.0 mmHg vs. TG 98.4±3.5 mmHg; p=NS). Pressor responses to infusion of 1.1 mg/kg/day AngII were also similar in WT and TG. These results suggest that endothelial Nox2 contributes to AngIIinduced endothelial dysfunction but has minimal effects on AngII-induced hypertension.