Age‐Associated Reductions in Endothelium‐Dependent Dilation in Humans are Related to Increases in Vascular Endothelial Protein Expression of Endothelin‐1

Endothelium-dependent dilation (EDD) is reduced with aging, but the underlying molecular mechanisms have not been established. To explore the possible role of changes in local vasoconstrictor and vasodilator proteins, we studied 42 younger (23 ± 1 years) and 41 older (63 ± 1 years) healthy men. EDD (brachial artery flow mediated dilation, FMD) was 50% lower in the older subjects. Plasma concentrations (6.3 ± 0.21 vs. 5.5 ± 0.14 pg/ml, P < 0.05) and vascular endothelial expression (0.47 ± 0.06 vs. 0.32 ± 0.03 ET-1/HUVEC intensity, P < 0.05, quantitative immuno-fluorescence) of the vasoconstrictor protein endothelin-1 (ET-1) were greater in the older vs. young men. Protein expression of endothelial nitric oxide synthase (eNOS) was lower (0.19 ± 0.02 vs. 0.27 ± 0.05 eNOS/HUVEC intensity, P = 0.07), whereas expression of ser1177 phosphorylated eNOS (p-eNOS), an activated form, was greater (0.82 ± 0.15 vs. 0.40 ± 0.06 p-eNOS/HUVEC intensity, P < 0.05) in the older vs. young men. In the overall group, FMD was inversely related to both plasma ET-1 (r = −0.25, P < 0.05) and vascular endothelial ET-1 (r = −0.37, P < 0.05), but not to eNOS or p-eNOS. These results indicate that the reduction in EDD with aging in healthy men is related to an increase in ET-1 protein expression in the vascular endothelium. Endothelial expression of p-eNOS is increased in older men, perhaps as a compensatory response to an age-associated reduction in eNOS protein. Supported by NIH AG013038, AG006537, AG022241, RR00051, and AG00279