title: COX-2-derived prostacyclin modulates vascular remodeling.
abstract: 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(2alpha)-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.
authors.affiliation: The Institute for Translational Medicine and Therapeutics, University of Pennsylvania, Philadelphia 19104, USA.
authors.forename: R Daniel
authors.initials: RD
authors.lastname: Rudic
authors.forename: Derek
authors.initials: D
authors.lastname: Brinster
authors.forename: Yan
authors.initials: Y
authors.lastname: Cheng
authors.forename: Susanne
authors.initials: S
authors.lastname: Fries
authors.forename: Wen-Liang
authors.initials: WL
authors.lastname: Song
authors.forename: Sandra
authors.initials: S
authors.lastname: Austin
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Coffman
authors.forename: Garret A
authors.initials: GA
authors.lastname: FitzGerald
mesh_terms: D000818:Animals; D001158:Arteries / Q000637:transplantation; D001161:Arteriosclerosis / Q000209:etiology; D001808:Blood Vessels / Q000187:drug effects / Q000502:physiology*; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000633:toxicity*; D011464:Epoprostenol / Q000502:physiology*; D006439:Hemodynamics; D006973:Hypertension / Q000209:etiology; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D011451:Prostaglandin-Endoperoxide Synthases / Q000502:physiology*; D044006:Receptors, Epoprostenol / Q000502:physiology; D044244:Receptors, Thromboxane A2, Prostaglandin H2 / Q000502:physiology; D013449:Sulfonamides / Q000633:toxicity
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D044006:Receptors, Epoprostenol; D044244:Receptors, Thromboxane A2, Prostaglandin H2; D013449:Sulfonamides; D011464:Epoprostenol; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C012655:nimesulide