Mechanical factors regulate both blood vessel growth and the development and progression of vascular disease. Acting on apoptotic and inflammatory signaling, the transcription factor nuclear factor κB (NF-κB) is a likely mediator of these processes. Nevertheless, pressure-dependent NF-κB activation pathways remain mostly unknown. Here we report that high intraluminal pressure induces reactive oxygen species (ROS) in arteries and that inhibition of NADPH oxidase prevents both the generation of ROS and the activation of NF-κB associated with high pressure. We also identify the epidermal growth factor receptor (EGFR) as a ROS-dependent signaling intermediate. In arteries from EGFR mutant mice (waved-2), pressure fails to activate NF-κB. Moreover, using vessels from EGFR ligand-deficient mice, we show that transforming growth factor (TGF)-α, but neither heparin-binding EGF-like growth factor nor epiregulin, transduces NF-κB activation by high pressure. Preventing the release of the active form of TGF-α also abolishes NF-κB induction by strain. The role of TGF-α signaling in vascular remodeling is substantiated in vivo; angiotensin II-induced activation of NF-κB and associated cell proliferation and wall thickening are much reduced in TGF-α–mutant mice compared with wild-type, despite equivalent hypertension in both groups. Conversely, apoptotic cells are detected only in vessels from hypertensive TGF-α–mutant mice, outlining the role of NF-κB in cell survival. Finally, the NF-κB activation pathway contrasts with that of extracellular signal-regulated kinase 1/2, which is activated by stretch through the EGFR but does not implicate TGF-α. Hence, our data identify TGF-α as a potential specific target to modulate mechanosensitive NF-κB activation and associated vascular remodeling.