Role of elevated EGFR phosphorylation in the induction of structural remodelling and altered mechanical properties of resistance artery from type 2 diabetic mice

Abstract

Background: Type 2 diabetes is associated with microvascular complications. We hypothesized that the sustained elevated EGFR phosphorylation produces structural wall remodelling and altered mechanical properties of mesenteric resistance artery (MRA) in type 2 diabetes.

Methods: Freshly isolated MRA (80-100 microm 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.

Results: Data indicated that MRA from diabetic mice have a smaller passive diameter than MRA from control mice under intra-luminal 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 remodelling index (38 +/- 5% vs control) revealed eutrophic structural remodelling of MRA from diabetic mice, which was strengthened with histology. Mechanical properties revealed a great strain-stress relationship in MRA from control versus 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 the type 2 diabetic mice when compared to control mice. Diabetic mice treated with EGFR inhibitor (AG1478, 10 mg/kg/day) for 2 weeks showed reduced EGFR phosphorylation, wall thickness, collagen type 1 content, and improved the altered mechanical properties of MRA.

Conclusion: These data provide evidence regarding the role of EGFR in morphological wall remodelling 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.