Involvement of EGF receptor with oxidative stress in type 2 diabetic mouse resistance artery dysfunction

Type 2 diabetes is associated with vasculopathy. We previously showed a role for EGF receptor (EGFR) in the control of myogenic tone (MT). We hypothesized that increased EGFR phosphorylation contributes to resistance artery dysfunction in type 2 diabetes. Methods and Results: Type 2 diabetic db−/db− (diabetic) and non‐diabetic Db−/db+ (control) mice were treated with the EGFR inhibitor (AG1478, 1 μM) for 2 weeks. Isolated mesenteric resistance arteries (MRAs) were mounted in an arteriograph. Pressure‐induced MT was increased in diabetic mice and was normalized by AG1478 treatment. Phenylephrine‐induced contraction and NO donor induced relaxation endothelium independent were similar in all groups. In diabetic mice, endothelium dependent relaxation in response to flow or acetylcholine was decreased and was associated with reduced eNOS protein expression. AG1478 treatment restored eNOS expression and improved endothelial function. RA cultured endothelial cells (EC) subjected to high glucose (HG 22mM) for 48 hrs showed decreased eNOS expression and phosphorylation in response to calcium ionophore. HG decreased anti‐oxidant protein (MnSOD) and increased pro‐oxidant protein (gp91phox) level leading to oxidative stress generation increase, as assessed by DHE staining and endothelial NADPH oxidase activity. The pre‐incubation of endothelial cells with AG1478 restored eNOS‐phosphorylation and expression as well as the balance between pro‐ and anti‐oxidant factors induced by high glucose. Conclusion: We provide evidence of a link between EGFR, oxidative stress and resistance artery endothelial and SMC dysfunction in type 2 diabetes.