H2O2 increases production of constrictor prostaglandins in smooth muscle leading to enhanced arteriolar tone in Type 2 diabetic mice

Abstract

Our previous study showed that arteriolar tone is enhanced in Type 2 diabetes mellitus (T2-DM) due to an increased level of constrictor prostaglandins. We hypothesized that, in mice with T2-DM, hydrogen peroxide (H2O2) is involved in the increased synthesis of constrictor prostaglandins, hence enhanced basal tone in skeletal muscle arterioles. Isolated, pressurized gracilis muscle arterioles (∼100 μm in diameter) of mice with T2-DM (C57BL/KsJ- db−/ db−) exhibited greater basal tone to increases in intraluminal pressure (20–120 mmHg) than that of control vessels (at 80 mmHg, control: 25 ± 5%; db/ db: 34 ± 4%, P < 0.05), which was reduced back to control level by catalase ( db/ db: 24 ± 4%). Correspondingly, in carotid arteries of db/ db mice, the level of dichlorofluorescein-detectable and catalase-sensitive H2O2 was significantly greater. In control arterioles, exogenous H2O2 (0.1–100 μmol/l) elicited dilations (maximum, 58 ± 10%), whereas in arterioles of db/ db mice H2O2 caused constrictions (−28 ± 8%), which were converted to dilations (maximum, 16 ± 5%) by the thromboxane A2/prostaglandin H2 (TP) receptor antagonist SQ-29548. In addition, arteriolar constrictions in response to the TP receptor agonist U-46619 were not different between the two groups of vessels. Endothelium denudation did not significantly affect basal tone and H2O2-induced arteriolar responses in either control or db/ db mice. Also, in arterioles of db/ db mice, but not in controls, 3-nitrotyrosine staining was detected in the endothelial layer of vessels. Thus we propose that, in mice with T2-DM, arteriolar production of H2O2 is enhanced, which leads to increased synthesis of the constrictor prostaglandins thromboxane A2/prostaglandin H2 in the smooth muscle cells, which enhance basal arteriolar tone. These alterations may contribute to disturbed regulation of skeletal muscle blood flow in Type 2 diabetes mellitus.