Elevated epidermal growth factor receptor phosphorylation induces resistance artery dysfunction in diabetic db/db mice.
OBJECTIVE
We previously showed epidermal growth factor receptor (EGFR) transactivation to be key mechanism in the regulation of resistance artery myogenic tone. Type 2 diabetes is associated with microvascular complications. We hypothesized that elevated EGFR phosphorylation contributes to resistance artery dysfunction in type 2 diabetes.


RESULTS
Diabetic db/db and nondiabetic (control) mice were treated with EGFR inhibitor (AG1478; 10 mg x kg(-1) x day(-1)) for 2 weeks. Isolated coronary artery and mesenteric resistance artery (MRA) were mounted in an arteriograph. Pressure-induced myogenic tone was increased in MRA and coronary artery from diabetic mice and normalized by AG1478. Phenylephrine-induced contraction and nitric oxide donor-induced relaxation were similar in all groups. Endothelium-dependent relaxation in response to shear stress and acetylcholine of MRA and coronary artery from diabetic mice was altered and associated with reduced endothelial nitric oxide synthase (eNOS) expression and phosphorylation. Treated diabetic mice with AG1478 improved coronary artery and MRA endothelial function and restored eNOS expression. Immunostaining and Western blot analysis showed increased endothelial and smooth muscle cell EGFR phosphorylation of MRA and coronary artery from diabetic mouse, which was reduced by AG1478. Primary cultured endothelial cells from resistance arteries treated with high glucose for 48 h showed an increase of EGFR phosphorylation associated with eNOS expression and phosphorylation decrease in response to calcium ionophore. Pretreatment of endothelial cells with AG1478 prevented the effect of high glucose.


CONCLUSIONS
This study provides evidence of the role of elevated EGFR phosphorylation in coronary artery and MRA dysfunction in diabetic db/db mice. Therefore, EGFR should be a potential target for overcoming diabetic small artery complications.
Belmadani
Souad
S
Department of Physiology, Louisiana State University Health Sciences Center, New Orleans, Louisiana, USA.
Palen
Desiree I
DI
Gonzalez-Villalobos
Romer A
RA
Boulares
Hamid A
HA
Matrougui
Khalid
K
D000818:Animals; D003331:Coronary Vessels / Q000503:physiopathology*; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D003925:Diabetic Angiopathies / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology*; D066246:ErbB Receptors / Q000187:drug effects* / Q000378:metabolism*; D008638:Mesenteric Arteries / Q000187:drug effects / Q000503:physiopathology; D051379:Mice; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010656:Phenylephrine / Q000494:pharmacology; D010766:Phosphorylation
D010656:Phenylephrine; D052250:Nitric Oxide Synthase Type III; D066246:ErbB Receptors