Published online before print April 27, 2006, doi: 10.1161/01.RES.0000224120.52792.10
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© 2006 American Heart Association, Inc.
Integrative Physiology |
Increased Expression of Cyclooxygenase-2 Mediates Enhanced Contraction to Endothelin ETA Receptor Stimulation in Endothelial Nitric Oxide Synthase Knockout Mice
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) ETA receptor-mediated smooth muscle contraction and, if so, to define the underlying mechanism(s). In isolated endothelium-denuded abdominal aortas, contractions to the selective ETA 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 ETA 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 ETA-mediated smooth muscle contraction. Furthermore, COX-2 expression is increased in eNOS–/– mice, which overcomes a reduced expression of ETA receptors and enables a selective increase in contraction to ETA receptor stimulation.
Key Words: endothelin-1(1-31) • arachidonic acid • thromboxane A2 • prostaglandin H2
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