Key result
Aortae from insulin-resistant ob/ob mice contracted in response to phenylephrine with roughly twice the force of control aortae, driven by increased contractility and impaired dilation.
In a diabetic mouse model, vascular dysfunction is driven by increased smooth muscle contractility and impaired dilation, with endothelium-produced prostaglandins contributing to the increased vasoconstriction.
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May prompt further preclinical vascular studies in insulin resistance; leaves open human translation.
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.
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Okon et al. (2003) studied Insulin resistance. Insulin resistance (ob/ob mouse model) vs. 57CBL/6J mice was evaluated on Vasomotor properties (contractile response and relaxation). Aortae from insulin-resistant ob/ob mice contracted in response to phenylephrine with roughly twice the force of control aortae, driven by increased contractility and impaired dilation.
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