Vascular COX-2 Modulates Blood Pressure and Thrombosis in Mice

Deletion of vascular COX-2 predisposes mice to thrombosis and hypertension. Chronicle of Some Deaths Foretold Nonsteroidal anti-inflammatory drugs (NSAIDs) relieve pain and inflammation by blocking the formation of prostaglandins due to the action of the enzymes cyclooxygenase-1 (COX-1) and COX-2. NSAIDs that inhibit COX-2 selectively are less likely to cause gastrointestinal side effects. More than a decade ago, it was discovered that such drugs depressed biosynthesis of prostaglandin I2 (PGI2, prostacyclin) in healthy human volunteers, as reflected by a decrease in its major metabolite PGI-M in urine. It was suggested that hemodynamic shear induced COX-2 expression in endothelial cells in vivo, accounting for the impact of the drug on PGI-M in urine. Based on the potentially cardioprotective effects of PGI2, a powerful platelet inhibitor and vasodilator in vitro, it was proposed that inhibition of COX-2 might confer a cardiovascular hazard. Subsequently, eight placebo-controlled trials of three structurally distinct COX-2 inhibitors established that there was an increased risk of myocardial infarction, stroke, hypertension, and heart failure in a subpopulation of patients taking these drugs. Despite these findings, there has been debate about the mechanistic underpinnings of this cardiovascular risk. In a study that helps to put this debate to rest, Yu et al. show that selective deletion of COX-2 in the vasculature of mice depresses PGI-M in mouse urine and predisposes them to both hypertension and thrombosis. Furthermore, expression of endothelial nitric oxide (NO) synthase and consequent release of NO are depressed if vascular COX-2 is deleted. This study provides clear evidence for a link between selective disruption of COX-2 in the vasculature and clinical outcomes in humans. Suppression of PGI2 formation due to deletion of vascular COX-2 is sufficient to explain the cardiovascular hazard from NSAIDs, which may be augmented by secondary mechanisms such as suppression of NO production. Prostacyclin (PGI2) 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 PGI2 (PGI-M) in the urine of healthy volunteers. This suggested that NSAIDs might cause adverse cardiovascular events by reducing production of cardioprotective PGI2. This prediction was based on the assumption that the concentration of PGI-M in urine likely reflected vascular production of PGI2 and that other cardioprotective mediators, especially nitric oxide (NO), were not able to compensate for the loss of PGI2. 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 PGI2 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.