| Abstrakt: |
Endothelium-dependent, nitric oxidemediated dilatation is impaired in aging arteries. The dysfunction reflects increased production of reactive oxygen species (ROS), is reversed by inhibiting superoxide with superoxide dismutase (SOD) mimics, and is assumed to reflect superoxide-mediated inactivation of nitric oxide. However, the dysfunction also reflects Src-dependent degradation and loss of vascular-endothelial (VE)-cadherin from adherens junctions, resulting in a selective impairment in the ability of the junctions to amplify endothelial dilatation. Experiments therefore tested the hypothesis that SOD mimics might restore endothelial dilation in aging arteries by inhibiting Src and protecting endothelial adherens junctions. Tail arteries from young and aging Fisher 344 rats were processed for functional (pressure myograph), biochemical (immunoblot), and morphological (immunofluorescence) analyses. Cellpermeable SOD mimics [manganese(III) tetrakis(1-methyl-4-pyridyl) porphyrin (MnTMPyP) or tempol] did not affect acetylcholine-induced dilatation in young arteries but increased responses and restored normal dilator function in aging arteries. In aging arteries, MnTMPyP decreased Src activity (immunoblots of Tyr416 phosphorylated compared with total Src), increased the intensity and width of VE-cadherin staining at endothelial junctions, and increased VE-cadherin levels in Triton X-100-insoluble lysates, which represents the junctional protein. Because of aging-induced junctional disruption, inhibiting VEcadherin clustering at adherens junctions with a function-blocking antibody does not affect acetylcholine-induced dilatation in aging arteries. However, the antibody prevented SOD mimics from restoring acetylcholine-induced dilatation in aging arteries. Therefore, SOD mimics improve impaired adherens junctions in aging endothelium, which is essential for SOD mimics to restore endothelium-dependent dilatation in aging arteries. The results suggest an important new pathological role for ROS in aging endothelium, namely, disruption of adherens junctions. [ABSTRACT FROM AUTHOR] |
