title: Pathologic endothelial response and impaired function of circulating angiogenic cells in patients with Fabry disease.
abstract: Fabry disease is an X-chromosomal recessive deficiency of the lysosomal hydrolase alpha-galactosidase A (alpha-Gal). This results in an accumulation of globotriaosylceramide (GL-3) in a variety of cells often with subsequent functional impairment. Here, the impact of Fabry disease on the biology of circulating angiogenic cells (CACs) and the endothelial response to transient ischemia was investigated. Untreated patients with Fabry disease (n = 26), patients after initiation of alpha-Gal enzyme replacement therapy (ERT) (n = 16) and healthy controls (n = 26) were investigated. Endothelial function was assessed by the EndoPAT2000 device. CAC numbers were assessed by flow-cytometry, CAC function by a modified Boyden chamber assay. Fabry patients showed a pathologic endothelial response, which normalized after ERT. CACs were increased in number, but functionally impaired. Immunofluorescence and electron microscopy identified an accumulation of GL-3 in Fabry CACs. ERT attenuated CAC dysfunction and improved markers of oxidative stress response in Fabry patients via a reduction in GL-3 accumulation in vitro and in vivo. Silencing of alpha-Gal in healthy CACs impaired their migratory capacity underlining a key role of this enzyme for CAC function. CAC supernatant as well as CACs from Fabry patients impaired angiogenesis and migratory capacity of HUVECs providing a mechanistic link between CAC and endothelial dysfunction. CAC adhesion to TNF-α pre-stimulated HUVECs and tube formation was impaired by alpha-Gal knockdown. Fabry patients show a dysfunction of CAC and a pathologic endothelial response. ERT improves CAC and endothelial function and thus may attenuate development of cardiovascular disease in the long term in this patient population.
authors.affiliation: Hannover Medical School, Institute of Molecular and Translational Therapeutic Strategies, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany.
authors.forename: Johan M
authors.initials: JM
authors.lastname: Lorenzen
authors.forename: Bernd
authors.initials: B
authors.lastname: Dietrich
authors.forename: Jan
authors.initials: J
authors.lastname: Fiedler
authors.forename: Virginija
authors.initials: V
authors.lastname: Jazbutyte
authors.forename: Felix
authors.initials: F
authors.lastname: Fleissner
authors.forename: Nicola
authors.initials: N
authors.lastname: Karpinski
authors.forename: Frank
authors.initials: F
authors.lastname: Weidemann
authors.forename: Christoph
authors.initials: C
authors.lastname: Wanner
authors.forename: Esther
authors.initials: E
authors.lastname: Asan
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Caprio
authors.forename: Georg
authors.initials: G
authors.lastname: Ertl
authors.forename: Johann
authors.initials: J
authors.lastname: Bauersachs
authors.forename: Thomas
authors.initials: T
authors.lastname: Thum
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000502:physiology*; D056947:Enzyme Replacement Therapy; D000795:Fabry Disease / Q000503:physiopathology* / Q000628:therapy; D005260:Female; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D018919:Neovascularization, Physiologic; D052250:Nitric Oxide Synthase Type III / Q000235:genetics; D014281:Trihexosylceramides / Q000378:metabolism; D000519:alpha-Galactosidase / Q000502:physiology
chemical_list: D014281:Trihexosylceramides; C018549:globotriaosylceramide; D052250:Nitric Oxide Synthase Type III; D000519:alpha-Galactosidase