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 kappaB (
NF-kappaB) is a likely mediator of these processes. Nevertheless, pressure-dependent
NF-kappaB 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-kappaB 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-kappaB. Moreover, using vessels from EGFR
ligand-deficient mice, we show that
transforming growth factor (
TGF)-alpha, but neither
heparin-binding EGF-like growth factor nor
epiregulin, transduces
NF-kappaB activation by high pressure. Preventing the release of the active form of
TGF-alpha also abolishes
NF-kappaB induction by strain. The role of
TGF-alpha signaling in
vascular remodeling is substantiated in vivo;
angiotensin II-induced activation of
NF-kappaB and associated cell proliferation and wall thickening are much reduced in
TGF-alpha-mutant mice compared with wild-type, despite equivalent
hypertension in both groups. Conversely, apoptotic cells are detected only in vessels from hypertensive
TGF-alpha-mutant mice, outlining the role of
NF-kappaB in cell survival. Finally, the
NF-kappaB 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-alpha. Hence, our data identify
TGF-alpha as a potential specific target to modulate mechanosensitive
NF-kappaB activation and associated
vascular remodeling.