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Chronic inhibition of epidermal growth factor receptor tyrosine kinase and extracellular signal-regulated kinases 1 and 2 (ERK1/2) augments vascular response to limb ischemia in type 2 diabetic mice

 Soo-Kyoung Choi  ;  Maria Galán  ;  Megan Partyka  ;  Mohamed Trebak  ;  Souad Belmadani  ;  Khalid Matrougui 
 AMERICAN JOURNAL OF PATHOLOGY, Vol.180(1) : 410-418, 2012 
Journal Title
Issue Date
Animals ; Blood Flow Velocity/physiology ; Blood Glucose/metabolism ; Body Weight/physiology ; Capillaries/physiology ; Cyclic GMP/metabolism ; Diabetes Mellitus, Type 2/blood ; Diabetes Mellitus, Type 2/physiopathology ; Diabetes Mellitus, Type 2/prevention & control* ; Diabetic Angiopathies/blood ; Diabetic Angiopathies/physiopathology ; Diabetic Angiopathies/prevention & control* ; Hindlimb/blood supply* ; Insulin/metabolism ; Ischemia/blood ; Ischemia/physiopathology ; Ischemia/prevention & control* ; Male ; Mice ; Nitric Oxide Synthase Type III/metabolism ; Phosphorylation ; RNA, Messenger/metabolism ; Receptor Protein-Tyrosine Kinases/antagonists & inhibitors* ; Receptor, Epidermal Growth Factor/antagonists & inhibitors* ; Vascular Endothelial Growth Factor A/metabolism
Type 2 diabetes is a key risk factor for ischemia-dependent pathology; therefore, a significant medical need exists to develop novel therapies that increase the formation of new vessels. We explored the therapeutic potential of epidermal growth factor receptor tyrosine kinase (EGFRtk) and extracellular signal-regulated kinase 1/2 (ERK1/2) inhibition in impaired ischemia-induced neovascularization in type 2 diabetes. Unilateral femoral artery ligation was performed in diabetic (db(-)/db(-)) and their control (db(-)/db(+)) mice for 4 weeks, followed by treatments with EGFRtk and ERK1/2 inhibitors (AG1478, 10 mg/kg/day and U0126, 400 μg/kg/day, respectively) for 3 weeks. Neovascularization, blood flow recovery, vascular and capillary density, and endothelial nitric oxide synthase activity were significantly impaired and were associated with enhanced EGFRtk and ERK1/2 activity in db(-)/db(-) mice. EGFRtk and ERK1/2 inhibitors did not have any effect in control mice, while in db(-)/db(-) mice there was a significant increase in neovascularization, blood flow recovery, vascular and capillary density, endothelial nitric oxide synthase activity, and were associated with a decrease in EGFRtk and ERK1/2 activity. Our data demonstrated that the inhibition of EGFRtk and ERK1/2 restored ischemia-induced neovascularization and blood flow recovery in type 2 diabetic mice. Thus, EGFRtk and ERK1/2 could be possible targets to protect from ischemia-induced vascular pathology in type 2 diabetes.
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1. College of Medicine (의과대학) > Dept. of Physiology (생리학교실) > 1. Journal Papers
Yonsei Authors
Choi, Soo Kyoung(최수경) ORCID logo https://orcid.org/0000-0002-7115-6358
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