Abstract
Thromboxane (Tx) A2 is a vasoconstrictor and platelet agonist. Aspirin affords cardioprotection through inhibition of TxA2 formation by platelet cyclooxygenase (COX-1). Prostacyclin (PGI2) is a vasodilator that inhibits platelet function. Here we show that injury-induced vascular proliferation and platelet activation are enhanced in mice that are genetically deficient in the PGI2 receptor (IP) but are depressed in mice genetically deficient in the TxA2 receptor (TP) or treated with a TP antagonist. The augmented response to vascular injury was abolished in mice deficient in both receptors. Thus, PGI2 modulates platelet-vascular interactions in vivo and specifically limits the response to TxA2. This interplay may help explain the adverse cardiovascular effects associated with selective COX-2 inhibitors, which, unlike aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs), inhibit PGI2 but not TxA2.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / pharmacology
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Animals
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Carotid Artery Injuries* / pathology
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Carotid Artery, Common / cytology
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Carotid Artery, Common / drug effects
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Carotid Artery, Common / physiology
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Cell Division
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Cyclooxygenase 2
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Cyclooxygenase 2 Inhibitors
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Cyclooxygenase Inhibitors / adverse effects
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Cyclooxygenase Inhibitors / therapeutic use
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Endothelium, Vascular / cytology
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Endothelium, Vascular / drug effects
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Endothelium, Vascular / physiology*
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Epoprostenol / metabolism
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Epoprostenol / physiology*
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Humans
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Isoenzymes / antagonists & inhibitors
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Lactones / adverse effects
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Lactones / therapeutic use
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Male
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Membrane Proteins
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Mice, Transgenic
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Muscle, Smooth, Vascular / cytology
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Muscle, Smooth, Vascular / drug effects
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Muscle, Smooth, Vascular / physiology
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Naphthalenes
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Platelet Activation* / drug effects
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Platelet Aggregation / drug effects
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Propionates
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Prostaglandin-Endoperoxide Synthases
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Receptors, Epoprostenol
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Receptors, Prostaglandin / physiology
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Receptors, Thromboxane / antagonists & inhibitors
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Receptors, Thromboxane / genetics
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Receptors, Thromboxane / physiology
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Sulfones
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Tetrahydronaphthalenes / pharmacology
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Thromboxane A2 / physiology*
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Tunica Intima / cytology
Substances
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Cyclooxygenase 2 Inhibitors
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Cyclooxygenase Inhibitors
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Isoenzymes
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Lactones
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Membrane Proteins
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Naphthalenes
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Propionates
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Receptors, Epoprostenol
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Receptors, Prostaglandin
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Receptors, Thromboxane
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Sulfones
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Tetrahydronaphthalenes
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rofecoxib
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Thromboxane A2
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15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid
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terutroban
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Epoprostenol
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Cyclooxygenase 2
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PTGS2 protein, human
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Prostaglandin-Endoperoxide Synthases