title: Vascular COX-2 modulates blood pressure and thrombosis in mice.
abstract: Prostacyclin (PGI(2)) is a vasodilator and platelet inhibitor, properties consistent with cardioprotection. More than a decade ago, inhibition of cyclooxygenase-2 (COX-2) by the nonsteroidal anti-inflammatory drugs (NSAIDs) rofecoxib and celecoxib was found to reduce the amount of the major metabolite of PGI(2) (PGI-M) in the urine of healthy volunteers. This suggested that NSAIDs might cause adverse cardiovascular events by reducing production of cardioprotective PGI(2). This prediction was based on the assumption that the concentration of PGI-M in urine likely reflected vascular production of PGI(2) and that other cardioprotective mediators, especially nitric oxide (NO), were not able to compensate for the loss of PGI(2). Subsequently, eight placebo-controlled clinical trials showed that NSAIDs that block COX-2 increase adverse cardiovascular events. We connect tissue-specific effects of NSAID action and functional correlates in mice with clinical outcomes in humans by showing that deletion of COX-2 in the mouse vasculature reduces excretion of PGI-M in urine and predisposes the animals to both hypertension and thrombosis. Furthermore, vascular disruption of COX-2 depressed expression of endothelial NO synthase and the consequent release and function of NO. Thus, suppression of PGI(2) formation resulting from deletion of vascular COX-2 is sufficient to explain the cardiovascular hazard from NSAIDs, which is likely to be augmented by secondary mechanisms such as suppression of NO production.
authors.affiliation: Institute for Translational Medicine and Therapeutics, University of Pennsylvania, Philadelphia, PA 19104, USA. yuying@sibs.ac.cn
authors.forename: Ying
authors.initials: Y
authors.lastname: Yu
authors.forename: Emanuela
authors.initials: E
authors.lastname: Ricciotti
authors.forename: Rosario
authors.initials: R
authors.lastname: Scalia
authors.forename: Soon Yew
authors.initials: SY
authors.lastname: Tang
authors.forename: Gregory
authors.initials: G
authors.lastname: Grant
authors.forename: Zhou
authors.initials: Z
authors.lastname: Yu
authors.forename: Gavin
authors.initials: G
authors.lastname: Landesberg
authors.forename: Irene
authors.initials: I
authors.lastname: Crichton
authors.forename: Weichen
authors.initials: W
authors.lastname: Wu
authors.forename: Ellen
authors.initials: E
authors.lastname: Puré
authors.forename: Colin D
authors.initials: CD
authors.lastname: Funk
authors.forename: Garret A
authors.initials: GA
authors.lastname: FitzGerald
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000502:physiology*; D001808:Blood Vessels / Q000201:enzymology* / Q000503:physiopathology*; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D011464:Epoprostenol / Q000096:biosynthesis; D017353:Gene Deletion; D006706:Homeostasis; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000378:metabolism; D009928:Organ Specificity; D013599:Systole; D013927:Thrombosis / Q000201:enzymology* / Q000503:physiopathology*
chemical_list: D009569:Nitric Oxide; D011464:Epoprostenol; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2