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(Circulation Research. 2006;98:1439.)
© 2006 American Heart Association, Inc.

Integrative Physiology

Increased Expression of Cyclooxygenase-2 Mediates Enhanced Contraction to Endothelin ET_A Receptor Stimulation in Endothelial Nitric Oxide Synthase Knockout Mice

Yingbi Zhou, Srabani Mitra^*, Saradhadevi Varadharaj^*, Narasimham Parinandi, Jay L. Zweier, Nicholas A. Flavahan

From the Davis Heart & Lung Research Institute, The Ohio State University, Columbus.

Correspondence to Yingbi Zhou, MD, PhD, Heart & Lung Research Institute, The Ohio State University, 473 W 12th Ave, Rm 545, Columbus, OH 43210. E-mail zhou-4{at}medctr.osu.edu

The aim of this study was to determine whether prolonged loss of NO activity, in endothelial NO synthase knockout (eNOS^–/–) mice, influences endothelin (ET) ET_A receptor-mediated smooth muscle contraction and, if so, to define the underlying mechanism(s). In isolated endothelium-denuded abdominal aortas, contractions to the selective ET_A receptor agonist ET-1(1-31) were significantly increased in aortas from eNOS^–/– compared with wild-type (WT) mice. In contrast, contractions to the ₁-adrenergic agonist phenylephrine or the thromboxane (TX) A₂ analog U-46619 were similar between eNOS^–/– and WT mice. Immunofluorescent and Western blot analysis demonstrated that the aortic expression of ET_A receptors was decreased in eNOS^–/– compared with WT mice. Contractions evoked by ET-1(1-31), but not phenylephrine, were reduced by inhibition of cyclooxygenase-2 (COX-2) (indomethacin or celecoxib) or of TXA₂/prostaglandin H₂ receptors (SQ-29548). After COX inhibition, contractions to ET-1(1-31) were no longer increased and were actually decreased in eNOS^–/– compared with WT aortas. Western blot analysis revealed that endothelium-denuded abdominal aortas express COX-2, but not COX-1, and that expression of COX-2 was significantly increased in eNOS^–/– compared with WT mice. Contractions to the COX substrate arachidonic acid were also increased in eNOS^–/– aortas. Furthermore, ET-1(1-31) but not phenylephrine stimulated production of the TXA₂ metabolite TXB₂, which was increased in eNOS^–/– compared with WT aortas. Therefore, COX-2 plays a crucial and selective role in ET_A-mediated smooth muscle contraction. Furthermore, COX-2 expression is increased in eNOS^–/– mice, which overcomes a reduced expression of ET_A receptors and enables a selective increase in contraction to ET_A receptor stimulation.

Key Words: endothelin-1(1-31) • arachidonic acid • thromboxane A₂ • prostaglandin H₂

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