Impaired angiogenesis in glutathione peroxidase-1-deficient mice is associated with endothelial progenitor cell dysfunction.
Several vascular disease are characterized by elevated levels of reactive oxygen species (ROS). Vascular endothelium is protected from oxidant stress by expressing enzymes such as glutathione peroxidase type 1 (GPx-1). In this study, we investigated the effect of vascular oxidant stress on ischemia-induced neovascularization in a murine model of homozygous deficiency of GPx-1. GPx-1-deficient mice showed impaired revascularization following hindlimb ischemic surgery based on laser Doppler measurements of blood flow and capillary density in adductor muscle. GPx-1-deficient mice also showed an impaired ability to increase endothelial progenitor cell (EPC) levels in response to ischemic injury or subcutaneous administration of vascular endothelial growth factor protein. EPCs isolated from GPx-1-deficient mice showed a reduced ability to neutralize oxidative stress in vitro, which was associated with impaired migration toward vascular endothelial growth factor and increased sensitivity to ROS-induced apoptosis. EPCs isolated from GPx-1-deficient mice were impaired in their ability to promote angiogenesis in wild-type mice, whereas wild-type EPCs were effective in stimulating angiogenesis in GPx-1-deficient mice. These data suggest that EPC dysfunction is a mechanism by which elevated levels of ROS can contribute to vascular disease.
Galasso
Gennaro
G
Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
Schiekofer
Stephan
S
Sato
Kaori
K
Shibata
Rei
R
Handy
Diane E
DE
Ouchi
Noriyuki
N
Leopold
Jane A
JA
Loscalzo
Joseph
J
Walsh
Kenneth
K
D000818:Animals; D017209:Apoptosis; D002454:Cell Differentiation; D042783:Endothelial Cells / Q000166:cytology / Q000201:enzymology / Q000502:physiology*; D005979:Glutathione Peroxidase / Q000172:deficiency / Q000502:physiology*; D006614:Hindlimb / Q000098:blood supply; D007511:Ischemia / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic; D018384:Oxidative Stress; D017382:Reactive Oxygen Species; D013234:Stem Cells / Q000201:enzymology / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology; D000094765:Glutathione Peroxidase GPX1
D017382:Reactive Oxygen Species; D042461:Vascular Endothelial Growth Factor A; D005979:Glutathione Peroxidase; D000094765:Glutathione Peroxidase GPX1; C000722068:Gpx1 protein, mouse