Decreased Nitric Oxide Bioavailability in a Mouse Model of Fabry Disease

Abstract

Fabry disease is a lysosomal storage disorder that results in an accumulation of globotriaosylceramide in vascular tissue secondary to a deficiency in ␣-galactosidase A. The glycolipid-associated vasculopathy results in strokes and cardiac disease, but the basis for these complications is poorly understood. Recent studies in the ␣-galactosidase A-knockout mouse suggested that a decrease in nitric oxide (NO) bioavailability may play a role in the abnormal thrombosis, atherogenesis, and vasorelaxation that are characteristic of these mice. To understand better the association between impaired NO bioavailability and glycolipid accumulation, we studied ␣-galactosidase A-knockout mice or primary cultures of their aortic endothelial cells. Treatment of knockout mice with a potent inhibitor of glucosylceramide synthase reversed accumulation of globotriaosylceramide but failed to normalize the defect in vasorelaxation. Basal and insulin-stimulated endothelial NO synthase (eNOS) activities in endothelial cells derived from knockout mice were lower than those observed from wild-type mice; normalization of glycolipid only partially reversed this reduction in eNOS activity. The loss of eNOS activity associated with a decrease in high molecular weight caveolin oligomers in endothelial cells and isolated caveolae, suggesting a role for glycolipids in caveolin assembly. Finally, concentrations of ortho-tyrosine and nitrotyrosine in knockout endothelial cells were markedly elevated compared with wild-type endothelial cells. These findings are consistent with a loss of NO bioavailability, associated with eNOS uncoupling, in the ␣-galactosidase A-knockout mouse.

Endothelial nitric oxide synthase uncoupling and microvascular dysfunction in the mesentery of mice deficient in α-galactosidase A

“…Consistent with previous findings in other vascular beds (5,22), we observed an age-dependent accumulation of Gb3 in the MAs of Gla-null, but not WT, mice. We also measured a significant reduction in the vasodilatory capacity of MA in Gla-deficient mice.…”

Multi-system disorders of glycosphingolipid and ganglioside metabolism

“…Gb3 accumulation in endothelium leads to vascular dysfunction, thereby providing an in vivo model to delineate the basis of cardio-and cerebrovascular complications associated with Fabry disease ( 139,140 ).…”

Kidney histologic alterations in α-Galactosidase-deficient mice

“…Gb3 storage at these sites correlates with the development of a complex vasculopathy, including thrombosis, atherogenesis, and endothelial dysfunction [20,[24][25][26][27][28]. Nevertheless, these mice have no clinical phenotype of Fabry disease [20].…”