Exacerbation of endothelial dysfunction in aged diabetic mice

Abstract

To test the hypothesis that aging accelerates endothelial dysfunction in type 2 diabetes mellitus, shear stress (SS)‐induced dilation (1, 10 and 20 dyne/cm2) and release of nitric oxide (NO) were determined in mesenteric arteries (~200–250 μm in diameter) isolated from three‐ (3M) and nine‐month (9M) old male db/db mice and their wild type (WT) controls. NO‐mediated SS‐induced dilation was significantly attenuated in arteries of 3M‐db/db mice and reduced further in those of 9M‐db/db mice compared to their age‐matched controls, in which, the dilation was comparable. SS‐stimulated release of nitrite was also significantly reduced in db/db mice compared to WT mice. Moreover, the magnitude of the reduction was greater in 9M compared to 3M‐db/db mice. Western blot analysis indicated significantly decreased SS‐induced phosphorylation of Akt (p‐Akt), as well as p‐eNOS, accounting for the reduced SS‐stimulated NO release and dilation in db/db mice compared to WT mice, and in 9M‐ compared to 3M‐db/db mice. Vascular superoxide production was significantly increased in 3M‐db/db and even more in 9M‐db/db mice. The levels of enhanced superoxide in both groups of db/db mice were proportional to increases in NOX‐2 protein expression. In conclusion, decreased NO bioavailability is responsible for the endothelial dysfunction in arteries of db/db mice that becomes further aggravated with aging (supported by NIH HL43023 and HL 070653).