A metalloprotease, ADAM17, mediates EGF receptor (EGFR) activation in vascular smooth muscle cells (VSMC) by angiotensin II (Ang II) leading to hypertrophy. dnADAM17 prevents vascular neointimal hyperplasia. To test if vascular ADAM17 silencing has any therapeutic potential against hypertension, we evaluated Ang II-induced end-organ damage as well as hypertension in ADAM17 flox/flox mice bred with sm22α Cre mice (Cre+/-). Upon Ang II infusion (1 μg/kg/min) for 2 weeks, control Cre-/- mice showed phenotypes of cardiac hypertrophy; HW/BW ratio (mg/g: 12.1±1.6 vs 6.2±0.4 p<0.05 n=8), cardiac echo (LVPWd mm: 0.96±0.05 vs 0.75±0.04, p<0.05) and plasma BNP (pg/mL: 1.94±0.36 vs 0.07±0.2, p<0.05) compared with saline infusion. Histological assessments demonstrated medial hypertrophy and perivascular fibrosis of coronary arteries with Ang II infusion. In contrast, these phenotypic changes were attenuated in VSMC ADAM17 silenced Cre+/- hearts with Ang II infusion; HW/BW ratio (7.0±0.8 vs 6.6±0.7 n=5), cardiac echo (LVPWd: 0.71±0.09 vs 0.65±0.09) and BNP (0.52±0.19 vs 0.03±0.003, p<0.05) compared with saline infusion. Control Cre-/- with Ang II infusion also demonstrated renal dysfunction assessed by BUN (mg/dL: 40.1±2.9 vs 23.0±2.8 p<0.05 n=6) compared with saline infusion, which was partially prevented in Cre+/- mice (30.4±2.5 vs 21.3±4.0 p<0.05). Renal fibrosis observed in Cre-/- with Ang II infusion was also attenuated in Cre+/- with Ang II infusion. However, Ang II induced hypertension in both Cre-/- and +/- mice assessed by radiotelemetry (MAP mmHg: 160±6 vs 155±7). Ang II infusion in Cre-/- enhanced ADAM17 and phospho-Tyr1068 EGFR staining in vasculatures of heart and kidney, whereas Ang II infused Cre+/- had diminished phospho-Tyr1068 EGFR staining and no ADAM17 staining in the vasculatures. qPCR analyses of cardiac ADAM17 mRNA in hearts further support these findings. In addition, IHC analyses revealed less oxidative stress and less ER stress in heart and kidney of Ang II-infused Cre-/- compared with Ang II-infused Cre+/-. These data suggest that vascular ADAM17/EGFR axis is critical for end organ damage via induction of ER/oxidative stress independent from blood pressure regulation.