Role of Elevated EGFR Phosphorylation in the Induction of Structural Remodeling and Altered Mechanical Properties of Resistance Artery from Type 2 Diabetic Mice

摘要

Type 2 diabetes is associated with microvascular complications. We hypothesized that the sustained elevated EGFR phosphorylation produces structural wall remodeling and altered mechanical properties of mesenteric resistance artery (MRA) in type 2 diabetes.Freshly isolated MRA (80–100 µm diameter) from type 2 diabetic (db⁻/db⁻, diabetic) and non-diabetic (db⁻/db⁺, control) mice were subjected to pressure-passive diameter and wall thickness relationships; western blot analysis and immunohistology.Data indicated that MRA from diabetic mice have a smaller passive diameter than MRA from control mice under intraluminal pressure range from 25 to 125 mmHg. Measurements of wall thickness:lumen diameter ratios (21±1.8 vs. 14±1.2 at 75 mmHg diabetic vs. control respectively), wall thickness and remodeling index (38±5% vs. control) revealed eutrophic structural remodeling of MRA from diabetic mice, which was strengthened with histology. Mechanical properties revealed a great strain-stress relationship in MRA from control vs. diabetic mice indicating increased stiffness in MRA from diabetic mice. Western blot analysis showed increased collagen type 1 content in a freshly isolated MRA from type 2 diabetic mice compared to control. Diabetic mice treated with EGFR inhibitor (AG1478, 10 mg/kg/day) for two weeks reduced EGFR phosphorylation, wall thickness, collagen type 1 content, and improved the altered mechanical properties of MRA.Conclusion and implicationsThese data provide evidence regarding the role of EGFR in morphological wall remodeling and altered mechanical properties of MRA from type 2 diabetic mice. This may identify new therapeutic targets for the control of vascular structure and therefore have important implications in type 2 diabetes.