title: Augmented contractile response of vascular smooth muscle in a diabetic mouse model.
abstract: The vasomotor properties of isolated aortae and mesenteric arteries of insulin-resistant ob/ob and 57CBL/6J mice were compared in organ bath studies. Vessels from ob/ob mice were more sensitive to phenylephrine. Pretreatment with L-NAME caused similar leftward shifts of the phenylephrine concentration response curves in diabetic and non-diabetic vessels. The ob/ob aortae contracted in response to phenylephrine with roughly twice the force while they were not stiffer than control aortae. L-NAME caused a greater percentage increase in maximal force in the control than in the ob/ob tissue. Denudation potentiated force in the control aortae, but not in the ob/ob aortae. Endothelium-dependent relaxation in the ob/ob aortae and mesenteric arteries was impaired as manifested by a decreased sensitivity and maximal relaxation to acetylcholine, while the aortic basal eNOS mRNA levels did not differ between the two strains. In addition, ob/ob aortae were less sensitive to the nitric oxide donor sodium nitroprusside. Inhibition of endogenous prostaglandin synthesis with indomethacin (10 microM) partly normalized the contractile response of the ob/ob aortae and enhanced their endothelium-dependent relaxation. Neither blockade of endothelin-1 receptors (bosentan, 10 microM) nor PKC inhibition (calphostin, 1 microM) affected the contractile response to phenylephrine in the mouse aortae of either strain. In conclusion, vascular dysfunction in the aorta and mesenteric artery of ob/ob mice are due to increased smooth muscle contractility and impaired dilation but not to changes in elasticity of the vascular wall. Endothelium-produced prostaglandins contribute to the increased vasoconstriction.
authors.affiliation: iCAPTUR(4)E Centre and Department of Pathology, University of British Columbia, Vancouver, Canada. eokon@mrl.ubc.ca
authors.forename: Elena B
authors.initials: EB
authors.lastname: Okon
authors.forename: Tania
authors.initials: T
authors.lastname: Szado
authors.forename: Ismail
authors.initials: I
authors.lastname: Laher
authors.forename: Bruce
authors.initials: B
authors.lastname: McManus
authors.forename: Cornelis
authors.initials: C
authors.lastname: van Breemen
mesh_terms: D000818:Animals; D001011:Aorta / Q000166:cytology / Q000502:physiology; D002452:Cell Count; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism / Q000503:physiopathology*; D004195:Disease Models, Animal; D004548:Elasticity; D005947:Glucose / Q000378:metabolism; D050356:Lipid Metabolism; D008638:Mesenteric Arteries / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009119:Muscle Contraction / Q000502:physiology*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000502:physiology*; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D011493:Protein Kinase C / Q000378:metabolism; D011509:Proteoglycans / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D017466:Receptors, Endothelin / Q000378:metabolism
chemical_list: D011509:Proteoglycans; D012333:RNA, Messenger; D017466:Receptors, Endothelin; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D011493:Protein Kinase C; D005947:Glucose