Published online before print May 19, 2005, doi: 10.1161/01.RES.0000170888.11669.28
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Submitted on February 2, 2005
Revised on May 10, 2005
Accepted on May 10, 2005
COX-2 Derived Prostacyclin Modulates Vascular Remodeling
R. Daniel Rudic ;
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.
* To whom correspondence should be addressed. 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 (the 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 (TxA2) 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 PGI2 receptor (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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