COX-2-derived prostacyclin modulates vascular remodeling

R. Daniel Rudic, Derek Brinster, Yan Cheng, Susanne Fries, Wen Liang Song, Sandra Austin, Thomas M. Coffman, Garret A. FitzGerald

Research output: Contribution to journalArticlepeer-review

104 Scopus citations


Suppression of prostacyclin (PGI2) biosynthesis may explain the increased incidence of myocardial infarction and stroke which has been observed in placebo controlled trials of cyclooxygenase (COX)-2 inhibitors. Herein, we examine if COX-2-derived PGI2 might condition the response of the vasculature to sustained physiologic stress in experimental models that retain endothelial integrity. Deletion of the PGI2 receptor (IP) or suppression of PGI2 with the selective COX-2 inhibitor, nimesulide, both augment intimal hyperplasia while preserving luminal geometry in mouse models of transplant arteriosclerosis or flow-induced vascular remodeling. Moreover, nimesulide or IP deletion augments the reduction in blood flow caused by common carotid artery ligation in wild-type mice. Generation of both thromboxane (Tx)A2 and the isoprostane, 8, 12 -iso iPF -VI, are increased in the setting of flow reduction and the latter increases further on administration of nimesulide. Deletion of the TxA2 receptor (TP) reduces the hyperplastic response to nimesulide and carotid ligation, despite further augmentation of TP ligand production. Suppression of COX-2-derived PGI2 or deletion of IP profoundly influences the architectural response of the vasculature to hemodynamic stress. Mechanism based vascular remodeling may interact with a predisposition to hypertension and atherosclerosis in contributing to the gradual transformation of cardiovascular risk during extended periods of treatment with selective inhibitors of COX-2.

Original languageEnglish (US)
Pages (from-to)1240-1247
Number of pages8
JournalCirculation research
Issue number12
StatePublished - Jun 24 2005
Externally publishedYes


  • Arteriosclerosis
  • Cyclooxygenase
  • Oxidant stress
  • Prostaglandins
  • Vascular remodeling

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine


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