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Hypertension is characterized by vascular remodeling and a propensity for atherosclerosis. Nuclear factor-kB (NF-kB) is a key regulator of these processes. To investigate mechanosensitive NF-kB activation pathways, we maintained mouse carotid arteries in organ culture during 24h at 80 or 150 mmHg. We found that high intraluminal pressure induces reactive oxygen species (ROS) in arteries, and that inhibition of NADPH oxidase with apocynin prevents both the generation of ROS (detected by hydroethidine staining) and the activation of NF-kB [substantiated by reduced levels of the NF-kB inhibitor IkBa (52±7% vs 100% at 80 mmHg; p<0.001) and increased phosphorylation of NF-kB (159±9%; p<0.05)] associated with high pressure. We also identified the epidermal growth factor receptor (EGFR) as a ROS-dependent signaling intermediate. In vessels at high pressure, both EGFR phosphorylation (265±36%; P<0.05) and NF-kB induction were abolished by the EGFR kinase inhibitor AG1478. These findings were confirmed using carotid arteries from EGFR kinase-deficient mice (waved-2), in which strain failed to activate NF-kB. Moreover, though pressure-dependent activation of NF-kB was maintained in vessels from mice deficient in EGFR ligands HB-EGF and epiregulin, absence of transforming growth factor alpha (TGFa) in waved-1 mice was associated with total inhibition of mechanosensitive NF-kB signaling. Interestingly, we found that strain also induced extracellular signal-regulated kinase (ERK)1/2 activation through the EGFR, but this occurred independently of TGFa, indicating that the pressure-dependent TGFa pathway targets NF-kB specifically. Hence our data demonstrate that strain-induced NF-kB requires TGFa as a signaling intermediate and identify TGFa as a likely effector of vascular wall alterations characteristic of hypertension.
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J. Vasc. Biol. 42, Sup:2 (2005) p115