Endothelial effects of 3-hydroxyglutaric acid: implications for glutaric aciduria type I.
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Endothelial effects of 3-hydroxyglutaric acid: implications for glutaric aciduria type I. / Mühlhausen, Chris; Ott, Nicola; Chalajour, Fariba; Tilki, Derya; Freudenberg, Folke; Shahhossini, Mona; Thiem, Joachim; Ullrich, Kurt; Braulke, Thomas; Ergün, Süleyman.
In: PEDIATR RES, Vol. 59, No. 2, 2, 2006, p. 196-202.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Endothelial effects of 3-hydroxyglutaric acid: implications for glutaric aciduria type I.
AU - Mühlhausen, Chris
AU - Ott, Nicola
AU - Chalajour, Fariba
AU - Tilki, Derya
AU - Freudenberg, Folke
AU - Shahhossini, Mona
AU - Thiem, Joachim
AU - Ullrich, Kurt
AU - Braulke, Thomas
AU - Ergün, Süleyman
PY - 2006
Y1 - 2006
N2 - 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.
AB - 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.
M3 - SCORING: Zeitschriftenaufsatz
VL - 59
SP - 196
EP - 202
JO - PEDIATR RES
JF - PEDIATR RES
SN - 0031-3998
IS - 2
M1 - 2
ER -
