title: 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.
abstract: 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.
authors: Department of Physiology, Hypertension and Renal Center of Excellence, Tulane University, New Orleans, Louisiana 70112, USA.
authors: Soo-Kyoung
authors: SK
authors: Choi
authors: Maria
authors: M
authors: Galán
authors: Megan
authors: M
authors: Partyka
authors: Mohamed
authors: M
authors: Trebak
authors: Souad
authors: S
authors: Belmadani
authors: Khalid
authors: K
authors: Matrougui
mesh_terms: D000818:Animals; D001783:Blood Flow Velocity / Q000502:physiology; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight / Q000502:physiology; D002196:Capillaries / Q000502:physiology; D006152:Cyclic GMP / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000503:physiopathology / Q000517:prevention & control*; D003925:Diabetic Angiopathies / Q000097:blood / Q000503:physiopathology / Q000517:prevention & control*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D006614:Hindlimb / Q000098:blood supply*; D007328:Insulin / Q000378:metabolism; D007511:Ischemia / Q000097:blood / Q000503:physiopathology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010766:Phosphorylation; D012333:RNA, Messenger / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D007328:Insulin; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D052250:Nitric Oxide Synthase Type III; D066246:ErbB Receptors; D020794:Receptor Protein-Tyrosine Kinases; D006152:Cyclic GMP