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Am J Physiol Heart Circ Physiol 296: H678-H688, 2009. First published December 26, 2008; doi:10.1152/ajpheart.00777.2008
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Chronic hypoxia enhances 15-lipoxygenase-mediated vasorelaxation in rabbit arteries

Nitin T. Aggarwal,1 Sandra L. Pfister,1 Kathryn M. Gauthier,1 Yuttana Chawengsub,1 John E. Baker,2 and William B. Campbell1

Departments of 1Pharmacology and Toxicology and 2Surgery (Cardiothoracic Surgery), Medical College of Wisconsin, Milwaukee, Wisconsin

Submitted 25 July 2008 ; accepted in final form 19 December 2008

15-Lipoxygenase (15-LO-1) metabolizes arachidonic acid (AA) to 11,12,15-trihydroxyeicosatrienoic acids (THETAs) and 15-hydroxy-11,12-epoxyeicosatrienoic acids (HEETA) that dilate rabbit arteries. Increased endothelial 15-LO-1 expression enhances arterial relaxations to agonists. We tested the effect of hypoxia on 15-LO-1 expression, THETA and HEETA synthesis, and relaxations in rabbit arteries. The incubation of rabbit aortic endothelial cells and isolated aortas in 0.7% O2 increased 15-LO-1 expression. Rabbits were housed in a hypoxic atmosphere of 12% O2 for 5 days. 15-LO-1 expression increased in the endothelium of the arteries of rabbits in 12% O2 compared with room air. THETA and HEETA synthesis was also enhanced in aortas and mesenteric arteries. AA hyperpolarized the smooth muscle cells in indomethacin- and phenylephrine-treated mesenteric arteries of hypoxic rabbits from –29.4 ± 1 to –50.1 ± 3 mV. The hyperpolarization to AA was less in arteries of normoxic rabbits (from –26.0 ± 2 to –37 ± 2 mV). This AA-induced hyperpolarization was inhibited by the 15-LO inhibitor BW-755C. Nitric oxide and prostaglandin-independent maximum relaxations to acetylcholine (79.7 ± 2%) and AA (38.3 ± 4%) were enhanced in mesenteric arteries from hypoxic rabbits compared with the normoxic rabbits (49.7 ± 6% and 19.9 ± 2%, respectively). These relaxations were inhibited by BW-755C and nordihydroguaiaretic acid. Therefore, hypoxia increased the relaxations to agonists in the rabbit mesenteric arteries by enhancing endothelial 15-LO-1 expression and synthesis of the hyperpolarizing factors THETA and HEETA.

endothelium; vasodilation; endothelium-derived hyperpolarizing factor


Address for reprint requests and other correspondence: S. L. Pfister, Dept. of Pharmacology and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Rd., Milwaukee, WI 53226 (e-mail: spfister{at}mcw.edu)






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