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


CONCLUSIONS
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.
Palen
Desiree I
DI
Department of Physiology, Hypertension and Renal Center of Excellence, Tulane University, 1430 Tulane Ave, New Orleans LA 70112, USA.
Matrougui
Khalid
K
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000503:physiopathology*; D003925:Diabetic Angiopathies / Q000473:pathology / Q000503:physiopathology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006720:Homozygote; D008297:Male; D008638:Mesenteric Arteries / Q000473:pathology / Q000502:physiology / Q000503:physiopathology*; D051379:Mice; D008820:Mice, Obese; D010766:Phosphorylation; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors; D011799:Quinazolines; D012016:Reference Values; D020032:Tyrphostins / Q000627:therapeutic use; D014655:Vascular Resistance / Q000502:physiology*
D011799:Quinazolines; D020032:Tyrphostins; C101044:RTKI cpd; D066246:ErbB Receptors; D017027:Protein Tyrosine Phosphatases