title: Endothelial effects of 3-hydroxyglutaric acid: implications for glutaric aciduria type I.
abstract: Infants with glutaric aciduria type 1 (GA1) are subject to intracranial vascular dysfunction. Here, we demonstrate that the disease-specific metabolite 3-hydroxyglutaric acid (3-OH-GA) inhibits basal and vascular endothelial growth factor (VEGF)-induced endothelial cell migration. 3-OH-GA affects the morphology of VEGF-induced endothelial tubes in vitro because of partial disintegration of endothelial cells. These effects correlate with Ve-cadherin loss. Remarkably, 3-OH-GA treatment of human dermal microvascular endothelial cells leads to disruption of actin cytoskeleton. Local application of 3-OH-GA alone or in combination with VEGF in chick chorioallantoic membrane induces abnormal vascular dilatation and hemorrhage in vivo. The study demonstrates that 3-OH-GA reduces endothelial chemotaxis and disturbs structural vascular integrity in vitro and in vivo. These data may provide insight in the mechanisms of 3-OH-GA-induced vasculopathic processes and suggest N-methyl-D-aspartate receptor-dependent and -independent pathways in the pathogenesis of GA1.
authors.affiliation: Department of Pediatrics, University of Hamburg, Germany.
authors.forename: Chris
authors.initials: C
authors.lastname: Mühlhausen
authors.forename: Nicola
authors.initials: N
authors.lastname: Ott
authors.forename: Fariba
authors.initials: F
authors.lastname: Chalajour
authors.forename: Derya
authors.initials: D
authors.lastname: Tilki
authors.forename: Folke
authors.initials: F
authors.lastname: Freudenberg
authors.forename: Mona
authors.initials: M
authors.lastname: Shahhossini
authors.forename: Joachim
authors.initials: J
authors.lastname: Thiem
authors.forename: Kurt
authors.initials: K
authors.lastname: Ullrich
authors.forename: Thomas
authors.initials: T
authors.lastname: Braulke
authors.forename: Süleyman
authors.initials: S
authors.lastname: Ergün
mesh_terms: D000199:Actins / Q000378:metabolism; D015703:Antigens, CD; D015820:Cadherins / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D005977:Glutarates / Q000378:metabolism* / Q000494:pharmacology*; D006801:Humans; D008661:Metabolism, Inborn Errors / Q000473:pathology*; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology; D000099152:Cadherin 5
chemical_list: D000199:Actins; D015703:Antigens, CD; D015820:Cadherins; D005977:Glutarates; D042461:Vascular Endothelial Growth Factor A; D000099152:Cadherin 5; C108959:3-hydroxyglutaric acid; C035736:glutaric acid