Pressure-Induced Vascular Activation of Nuclear Factor-κB

Abstract

The effects of mechanical factors on nuclear factor (NF)-κB activation and its potential functional roles have been very little explored in the intact vessel. Thus, we chose to study the regulation of NF-κB 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-κB 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-κB inhibitor IκBα 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-κB, we evaluated the rate of apoptosis (TUNEL method) in carotid arteries cultured with or without an inhibitor peptide blocking nuclear translocation of NF-κB. No apoptosis was detected in control arteries either at 80 or 150 mm Hg. However, in the presence of the NF-κB 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-κB inhibitor peptide, which was additionally enhanced in treated vessels at 150 mm Hg. Our findings demonstrate that high intraluminal pressure activates NF-κB in arteries. Moreover, the activation of NF-κB seems to play a key role in preventing apoptosis in vascular cells, especially when vessels are exposed to high intraluminal pressure.