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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:1596.)
© 2005 American Heart Association, Inc.

Vascular Biology

GLUT4 Facilitative Glucose Transporter Specifically and Differentially Contributes to Agonist-Induced Vascular Reactivity in Mouse Aorta

James L. Park; Robert D. Loberg; Damon Duquaine; Hongyu Zhang; Baljit K. Deo; Noelia Ardanaz; Jami Coyle; Kevin B. Atkins; MaryLee Schin; Maureen J. Charron; Arno K. Kumagai; Patrick J. Pagano; Frank C. Brosius, III

From the Departments of Internal Medicine (J.L.P., R.D.L., D.D., H.Z., B.KD., J.C., K.B.A., M.S., A.K.K., F.C.B.) and Physiology (R.D.L., F.C.B.), University of Michigan Medical School, Ann Arbor, Mich; the Department of Biochemistry (M.J.C.), Albert Einstein College of Medicine, Bronx, NY; and the Hypertension and Vascular Research Division (N.A., P.J.P.), Henry Ford Hospital, Detroit, Mich.

Correspondence to Frank C. Brosius, III, University of Michigan, 1560 MSRB2, 1150 W Medical Center Dr, Ann Arbor, MI 48109-0676. E-mail fbrosius{at}umich.edu

Objective— We hypothesized that GLUT4 is a predominant facilitative glucose transporter in vascular smooth muscle cells (VSMCs), and GLUT4 is necessary for agonist-induced VSMC contraction.

Methods and Results— Glucose deprivation and indinavir, a GLUT4 antagonist, were used to assess the role of GLUT4 and non-GLUT4 transporters in vascular reactivity. In isolated endothelium-denuded mouse aorta, 50% of basal glucose uptake was GLUT4-dependent. Norepinephrine-mediated contractions were dependent on both GLUT4 and non-GLUT4 transporters, serotonin (5-HT)-mediated contractions were mainly GLUT4-dependent, and prostaglandin (PG) F₂-mediated contractions were dependent on non-GLUT4 transporters, whereas indinavir had no effect in GLUT4 knockout vessels. We also observed a 46% decrease in GLUT4 expression in aortas from angiotensin II hypertensive mice. Indinavir caused a less profound attenuation of maximal 5-HT–mediated contraction in these vessels, corresponding to the lower GLUT4 levels in the hypertensive aortas. Finally, and somewhat surprisingly, chronic GLUT4 knockout was associated with increased vascular reactivity compared with that in wild-type animals, suggesting that chronic absence or reduction of GLUT4 expression in VSMCs leads to opposite effects observed with acute inhibition of GLUT4.

Conclusions— Thus, we conclude that GLUT4 is constitutively expressed in large arteries and likely participates in basal glucose uptake. In addition, GLUT4, as well as other non-GLUT4 facilitative glucose transporters, are necessary for agonist-induced contraction, but each transporter participates in VSMC contraction selectively, depending on the agonist, and changes in GLUT4 expression may account for some of the functional changes associated with vascular diseases like hypertension.

We found that GLUT4 is a predominant transporter in VSMCs, and that GLUT4, as well as non-GLUT4 transporters, are necessary for agonist-induced VSMC contraction. However, each transporter participates in VSMC contraction selectively, depending on the agonist. Decreased GLUT4 expression may account for some functional changes associated with vascular diseases such as hypertension.

Key Words: glucose • GLUT4 • indinavir • vascular smooth muscle

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