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1 Laboratory for Physiology, VU University medical center, Amsterdam, The Netherlands
2 Department of Internal Medicine, VU University medical center, Amsterdam, The Netherlands
* To whom correspondence should be addressed. E-mail: e.eringa{at}vumc.nl.
Background. Insulin exerts both NO-dependent vasodilator and endothelindependent vasoconstrictor effects on skeletal muscle arterioles. The intracellular enzymes 1-Phosphatidylinositol 3-Kinase (PI3-kinase) and Akt have been shown to mediate vasodilator effects of insulin, but the signaling molecules involved in insulin's vasoconstrictor effects in these arterioles are unknown. Objective: To identify intracellular mediators of acute vasoconstrictor effects of insulin on skeletal muscle arterioles. Methods/Results. Rat cremaster first order arterioles (n = 40) were isolated and vasoreactivity to insulin was studied in a pressure myograph. Insulin induced dose-dependent vasoconstriction of skeletal muscle arterioles (up to -22 ± 3 percent of basal diameter, P < 0.05) during PI3-kinase inhibition with wortmannin (50 nmol/L). Insulin-induced vasoconstriction was abolished by inhibition of extracellular signalregulated kinase 1/2 (ERK1/2), with PD98059 (40 micromol/L). In addition, inhibition of ERK1/2 without PI3-kinase inhibition uncovered insulin- mediated vasodilatation in skeletal muscle arterioles (up to 37 ± 10 percent of baseline diameter, P < 0.05). Effects of insulin on ERK1/2 activation in arterioles were then analyzed by Western blot. Insulin induced a transient, 2.4-fold increase in ERK1/2 phosphorylation (maximal around 15 minutes) in skeletal muscle arterioles (P < 0.05). Removal of the arteriolar endothelium abolished insulin-induced vasoconstriction, suggesting that activation of ERK1/2 in endothelial cells is involved in acute insulin-mediated vasoconstriction. To investigate this, acute effects of insulin on ERK1/2 phosphorylation were studied in human microvascular endothelial cells (MVEC). In support of the findings in skeletal muscle arterioles, insulin induced a 1.9-fold increase in ERK1/2 phosphorylation (maximal around 15 minutes) in MVEC (P < 0.05). Conclusions. Acute vasoconstrictor effects of insulin in skeletal muscle arterioles are mediated by activation of ERK1/2 in endothelium. This ERK1/2-mediated vasoconstrictor effect antagonizes insulin-induced, PI3-kinase-dependent vasodilatation in skeletal muscle arterioles. These findings provide a novel mechanism by which insulin may determine blood flow and glucose disposal in skeletal muscle.
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