The lysosomal storage disorder Fabry disease is characterized by excessive 
globotriaosylceramide (Gb3) accumulation in major organs such as the heart and 
kidney. Defective lysosomal alpha-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 previously demonstrated that 
excessive vascular Gb3 in a mouse model of Fabry disease, the Gla-knockout 
(Gla(-/0)) mouse, results in abnormal vascular function, which includes abnormal 
endothelium-dependent contractions, a vascular phenomenon known to involve 
cyclooxygenase (COX). Therefore, we hypothesized that the vasculopathy in the 
Gla knockout mouse may be due to a vasoactive COX-derived product. To test this 
hypothesis, vascular reactivity experiments were performed in aortic rings from 
wild-type (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 with untreated Gla(-/0) rings, whereas COX inhibitors had 
no effect on contractility in endothelium-denuded rings. Nonspecific inhibition 
of COX with indomethacin (10 micromol/l) or COX1 inhibition with valeryl 
salicylate (3 mmol/l) improved endothelial function in rings from Gla(-/0) mice, 
but COX2 inhibition with NS-398 (1 micromol/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 vasopressor and vasorelaxant products, which contribute 
to the Fabry-related vasculopathy.