Pressure-induced vascular activation of nuclear factor-kappaB: role in cell survival.
The effects of mechanical factors on nuclear factor (NF)-kappaB activation and its potential functional roles have been very little explored in the intact vessel. Thus, we chose to study the regulation of NF-kappaB by intraluminal pressure using an organ culture model of mouse carotid arteries maintained at 80 or 150 mm Hg during 24 hours. Gel shift analysis revealed an increase in the DNA-binding capacity of NF-kappaB in vessels at high pressure compared with vessels at normal pressure (304+/-49%; P<0.001). This coincided with reduced levels of the endogenous NF-kappaB inhibitor IkappaBalpha in arteries at 150 mm Hg (52+/-7%; P<0.001), as detected by Western blot. To study the functional role of the pressure-induced activation of NF-kappaB, we evaluated the rate of apoptosis (TUNEL method) in carotid arteries cultured with or without an inhibitor peptide blocking nuclear translocation of NF-kappaB. No apoptosis was detected in control arteries either at 80 or 150 mm Hg. However, in the presence of the NF-kappaB inhibitor peptide, we observed apoptosis in vessels at 80 mm Hg (5+/-1%; P<0.001 versus untreated controls), which was markedly increased in vessels at 150 mm Hg (14+/-2%; P<0.001). These results were corroborated by immunohistochemical analysis showing positive staining for cleaved caspase 3 in vessels at 80 mm Hg treated with the NF-kappaB inhibitor peptide, which was additionally enhanced in treated vessels at 150 mm Hg. Our findings demonstrate that high intraluminal pressure activates NF-kappaB in arteries. Moreover, the activation of NF-kappaB seems to play a key role in preventing apoptosis in vascular cells, especially when vessels are exposed to high intraluminal pressure.
Lemarié
Catherine A
CA
Inserm U541, Hôpital Lariboisière, 41, Boulevard de la Chapelle, 75010 Paris.
Esposito
Bruno
B
Tedgui
Alain
A
Lehoux
Stéphanie
S
D000818:Animals; D001794:Blood Pressure / Q000502:physiology*; D002339:Carotid Arteries / Q000378:metabolism / Q000502:physiology*; D002470:Cell Survival / Q000502:physiology; D004247:DNA / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D020672:I-kappa B Proteins / Q000378:metabolism; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D040542:Mechanotransduction, Cellular / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation; D011312:Pressure; D013314:Stress, Mechanical
C083487:I kappa B beta protein; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606205:Nfkbia protein, mouse; D000072000:NF-KappaB Inhibitor alpha; D004247:DNA