title: Two distinct dysfunctions in diabetic mouse mesenteric artery contraction are caused by changes in the Rho A-Rho kinase signaling pathway.
abstract: Diabetic complications are associated with small artery dysfunctions. The objective of this study was to identify differences in endothelial cell-denuded mesenteric artery second branch (mesenteric artery-2) contraction, as a typical small artery, between diabetic and non-diabetic mice. Contractile responses in mesenteric artery-2 were assessed in male type 2 diabetic ob/ob mice aged 16-22 weeks and in age-matched control (Lean) mice. Phenylephrine induced dose-dependent contractions in Lean mice (1126.8 ± 28.6 mN/mm tissue at 10 μM phenylephrine; n=5), which were significantly reduced in ob/ob mice (716.8 ± 40.8 mN/mm at 10 μM phenylephrine; n=5). Exposure to high glucose (HG; twice the normal glucose [NG] concentration) enhanced phenylephrine-induced contraction in Lean (1341.4 ± 15.5 mN/mm; n=5) but not in ob/ob mice. These dysfunctions did not involve α(1)-receptor sensitization or protein kinase activity, although the calcium sensitivity of contraction was decreased in ob/ob mice. The Rho kinase inhibitor Y27632 suppressed the difference between Lean and ob/ob mice under NG conditions, which was accompanied by Rho A inactivation. Under HG conditions, glucose-dependent Rho A activation persisted in ob/ob mice whereas Rho kinase expression was reduced. These data suggest that inactivation of Rho A reduced contractibility under NG conditions, and the lack of glucose dependency is associated with reduced Rho kinase expression.
authors.affiliation: Department of Pharmacology, School of Pharmacy, Showa University, Tokyo, Japan. kojinobe@pharm.showa-u.ac.jp
authors.forename: Koji
authors.initials: K
authors.lastname: Nobe
authors.forename: Terumasa
authors.initials: T
authors.lastname: Hashimoto
authors.forename: Kazuo
authors.initials: K
authors.lastname: Honda
mesh_terms: D058646:Adrenergic alpha-1 Receptor Agonists / Q000494:pharmacology; D000818:Animals; D001160:Arterioles / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D020013:Calcium Signaling / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000150:complications* / Q000503:physiopathology; D003925:Diabetic Angiopathies / Q000097:blood / Q000150:complications / Q000378:metabolism / Q000503:physiopathology*; D015536:Down-Regulation / Q000187:drug effects; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D006943:Hyperglycemia / Q000209:etiology*; D066298:In Vitro Techniques; D008297:Male; D017537:Mesenteric Artery, Inferior / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009765:Obesity / Q000150:complications; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
chemical_list: D058646:Adrenergic alpha-1 Receptor Agonists; D047428:Protein Kinase Inhibitors; D014662:Vasoconstrictor Agents; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein