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(Circulation Research. 2005;96:1240.)
© 2005 American Heart Association, Inc.

Molecular Medicine

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

From the Institute for Translational Medicine and Therapeutics (R.D.R., Y.C., S.F., W.-L.S., G.A.F.), University of Pennsylvania, Philadelphia; and the Department of Medicine, Duke University and Durham Veterans Affairs Medical Centers (T.M.C.), Durham, NC.

Correspondence to Dr Garret FitzGerald, The Institute for Translational Medicine and Therapeutics, 421 Curie Blvd, Philadelphia, PA, 19104. E-mail garret{at}spirit.gcrc.upenn.edu

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 iPF₂-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.

Key Words: vascular remodeling • cyclooxygenase • oxidant stress • arteriosclerosis • prostaglandins

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