Increased expression of cyclooxygenase-2 mediates enhanced contraction to endothelin ETA receptor stimulation in endothelial nitric oxide synthase knockout mice

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

Research output: Contribution to journalArticlepeer-review

Abstract

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 α1-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.

Original languageEnglish (US)
Pages (from-to)1439-1445
Number of pages7
JournalCirculation research
Volume98
Issue number11
DOIs
StatePublished - Jun 2006
Externally publishedYes

Keywords

  • Arachidonic acid
  • Endothelin-1(1-31)
  • Prostaglandin H
  • Thromboxane A

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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