The lysosomal storage disorder, Fabry disease, is characterized by excessive globotriaosylceramide (Gb3) accumulation in major organs such as the heart and kidney. Defective lysosomal -galactosidase A (Gla) is responsible for excessive Gb3 accumulation, and one cell sensitive to the effects of Gb3 accumulation is vascular endothelium. Endothelial dysfunction is associated with Fabry disease and excessive cellular Gb3. We have previously demonstrated that excessive vascular Gb3 in a mouse model of Fabry disease, the Gla knockout (Gla -/0) mouse, has abnormal vascular function, which includes abnormal endothelium-dependent contractions, a vascular phenomenon known to involve cyclo-oxygenase (COX). Therefore we hypothesized that the vasculopathy in the Gla knockout mouse may be due to a vasoactive cyclooxygenase-derived product. To test this hypothesis, reactivity was performed in aortic rings from wildtype (Gla +/0) and Gla -/0 mice in the presence and absence of specific and nonspecific COX inhibitors. Specific inhibition of COX1 or COX2 in endothelium-intact rings from Gla -/0 mice decreased overall phenylephrine contractility compared to untreated Gla -/0 rings, whereas COX inhibitors had no effect on contractility in endothelium-denuded rings. Nonspecific inhibition of COX with indomethacin (10 µmoles/L) or COX1 inhibition with valeryl salicylate (3mmoles/L) improved endothelial function in rings from Gla -/0 mice, but COX2 inhibition with NS-398 (1 µmole/L) further increased endothelial dysfunction in rings from Gla -/0 mice. These results suggest that, in the Gla -/0 mice, COX1 and COX2 activity are increased and localized in the endothelium, producing both vasopressor and vasorelaxant products which contribute to the Fabry-related vasculopathy.