Transforming growth factor-alpha mediates nuclear factor kappaB activation in strained arteries.
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.
Lemarié
Catherine A
CA
Inserm U689, Centre de Recherche Cardiovasculaire Inserm Lariboisière, 41, Boulevard de la Chapelle, 75010 Paris, France.
Tharaux
Pierre-Louis
PL
Esposito
Bruno
B
Tedgui
Alain
A
Lehoux
Stéphanie
S
D000818:Animals; D002339:Carotid Arteries; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000502:physiology*; D066246:ErbB Receptors / Q000235:genetics / Q000502:physiology; D051379:Mice; D008817:Mice, Mutant Strains; D016328:NF-kappa B / Q000378:metabolism*; D009924:Organ Culture Techniques; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D013314:Stress, Mechanical; D016211:Transforming Growth Factor alpha / Q000502:physiology*
D016328:NF-kappa B; D017382:Reactive Oxygen Species; D016211:Transforming Growth Factor alpha; D066246:ErbB Receptors