α-galactosidase A deficiency promotes von Willebrand factor secretion in models of Fabry disease

Abstract

Fabry disease results from loss of activity of the lysosomal enzyme α-galactosidase A (GLA), leading to the accumulation of globoseries glycosphingolipids in vascular endothelial cells. Thrombosis and stroke are life-threatening complications of Fabry disease; however, the mechanism of the vasculopathy remains unclear. We explored the relationship between GLA deficiency and endothelial cell von Willebrand factor (VWF) secretion in in vivo and in vitro models of Fabry disease. Plasma VWF was significantly higher at two months and increased with age in Gla-null compared to wild-type mice. Disruption of GLA in a human endothelial cell line by siRNA and CRISPR/Cas9 resulted in a 3-fold and 5-fold increase in VWF secretion, respectively. The increase in VWF levels was associated with decreased endothelial nitric oxide synthase (eNOS) activity in both in vitro models. Pharmacological approaches that increase nitric oxide bioavailability or decrease reactive oxygen species completely normalized the elevated VWF secretion in GLA deficient cells. In contrast, the abnormality was not readily reversed by recombinant human GLA or by inhibition of glycosphingolipid synthesis with eliglustat. These results suggest that GLA deficiency promotes VWF secretion through eNOS dysregulation, which may contribute to the vasculopathy of Fabry disease.

Biomarkers in Fabry Disease. Implications for Clinical Diagnosis and Follow-up

“…Increased reactive oxygen species (ROS) and decreased nitric oxide (NO) also contribute to endothelial damage [24][25][26]. A different hypothesis about the development of vasculopathy, proposes that the accumulation of endothelial Gb3 causes a dysregulation of the enzyme nitric oxide endothelial synthase (eNOS) with the consequent formation of oxidant species derived from NO, which could be direct markers of vasculopathy in FD [27][28][29][30][31][32][33][34]. In addition, Gb3 could also contribute to endothelial damage from other different pathogenic mechanisms related to KCa3.1 channel dysfunction [35,36].…”

Progress in the understanding and treatment of Fabry disease

“…Proinflammatory cytokines have been implicated as a predisposing factor for thrombosis [68], stimulating the release of soluble prothrombotic markers, such as von Willebrand factor, and upregulating the expression of endothelial adhesion molecules [69,70]. In fact, both increases in von Willebrand factor and the expression of endothelial adhesion molecules have been observed in patients and mouse models of the disease [71,72]. Gb3 accumulation also promotes cell death pathways [73].…”

Fabry disease patients have an increased risk of stroke in the COVID-19 ERA. A hypothesis

“…There is a procoagulant and proinflammatory status in patients with FD manifested by endothelial cell activation, increased release of microparticles, activation of plasminogen, and, in some patients, elevation of D-dimer-products of fibrinogen breakdown [15] , [64] , [65] . In addition there is evidence of dysfunctional platelets favouring thrombosis and higher secretion of von Willebrand factor by endothelial cells in FD models [66] .…”