Abstract 378: Microvascular Endothelial Dysfunction and Age-Dependent Endothelial Activation in Mice with Fabry Disease

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Fabry disease, a lysosomal storage disorder, leads to an age-dependent accumulation of globotriaosylceramide (Gb3) in vascular tissue that ultimately causes cardiac disease and strokes. It has been demonstrated that this accumulation of Gb3 is consistent with a decrease in nitric oxide bioavailability and an impaired endothelial function in macrovessels including the aorta. Based on this, we hypothesized that microvessels would also have vascular dysfunction in older Fabry disease mice. To evaluate this, 8 month old wild-type (WT) and alpha-galactosidase A deficient (Fabry; FA) mice (n=4 / group) were euthanized, and mesenteric artery function was tested using a pressure myograph. Vessels from WT relaxed with Ach in a dose-dependent manner, while FA vessels were nearly devoid of Ach-mediated dilatation. The maximum relaxation with the highest dose of Ach (10^-4 M) was significantly different between groups (WT: 59 ± 11 %; FA: 1 ± 12 %; p=0.0004). However, endothelium-independent relaxation mediated by sodium nitroprusside was similar in vessels from both groups (WT: 81 ± 10 %; FA: 70 ± 9 %; p=0.15), confirming that the smooth muscle layer was intact and functional. Given the similar macro- and microvascular endothelial dysfunction evident in FA, we sought to identify serum measures of endothelial activation that could be used as a surrogate determinant of the age-dependent vascular dysfunction. We collected serum from age-matched WT and FA between 2 and 17 months of age (n=4-8 / group). We observed a significant age-dependent rise in FA for several serum markers of endothelial activation including soluble e-selectin, p-selectin and vascular cell adhesion molecule. However, von willebrand factor (vWF) provided the most sensitive age- and genotype-dependent changes between WT and FA (p=0.046 at 2 months and p=0.0004 at 17 months between groups). In conclusion, the data provide evidence of microvascular endothelial dysfunction in FA, demonstrated by a prominent defect in the mesenteric artery at 8 months of age. In addition, a robust age-dependent rise in vWF observed in FA suggests that this marker of endothelial activation might serve as a sensitive surrogate measure of endothelial dysfunction in therapeutic studies of Fabry disease.