Research ArticleCardiovascular Disease

Vascular COX-2 Modulates Blood Pressure and Thrombosis in Mice

Science Translational Medicine  02 May 2012:
Vol. 4, Issue 132, pp. 132ra54
DOI: 10.1126/scitranslmed.3003787

You are currently viewing the editor's summary.

View Full Text

Log in


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.