Nox4 is a NADPH oxidase ubiquitously expressed in vascular cells. Different to all other Noxes, Nox4 constitutively produces H₂O₂. We hypothesize that this basal H₂O₂ formation desensitizes against redox-mediated signaling of cytokines and growth factors. We generated tamoxifen-inducible Nox4^-/- mice. Tamoxifen-treatment induced a robust reduction of Nox4 in organs and cultured lung endothelial cells of these mice. Amplex red assay revealed reduced basal H₂O₂ formation. In vivo treatment with angiotensin II (AngII) revealed no difference between WT and Nox4^-/- mice with respect to hypertension development. However, when we acutely deleted Nox4 by tamoxifen an attenuation of vascular function in response to AngII was observed: Compared to WT animals, aortae from acutely Nox4-deficient animals had higher mass and medial hypertrophy in response to AngII. Loss of Nox4 increased the AngII-induced attenuation of endothelium-dependent relaxation in aortic rings. Importantly, as judged by qRT-PCR, a significantly greater degree of inflammation was present in acutely Nox4-deficient mice in response to AngII as documented by a greater expression of IL-1b, IL-6, TNF-a and TGFb1 and the macrophage marker EMR-1. Further acute loss of Nox4 resulted in a lowering of nitric oxide and carbon monoxide via downregulation of eNOS and hemeoxygenase. Interestingly inhibition of Nox4 induced an upregulation of E-Selectin surface abundance which lead to an enhanced macrophage adhesion to endothelial cells. We conclude that the constitutive H₂O₂ formation by Nox4 adjusts the vascular redox-balance and protects vessels from vascular remodeling and inflammation induced by AngII.