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(Circulation Research. 2006;98:254.)
© 2006 American Heart Association, Inc.

Integrative Physiology

Impaired Angiogenesis in Glutathione Peroxidase-1–Deficient Mice Is Associated With Endothelial Progenitor Cell Dysfunction

Gennaro Galasso^*, Stephan Schiekofer^*, Kaori Sato, Rei Shibata, Diane E. Handy, Noriyuki Ouchi, Jane A. Leopold, Joseph Loscalzo, Kenneth Walsh

From The Whitaker Cardiovascular Institute (C.G., S.S., K.S., R.S., N.O., K.W.), Boston University School of Medicine, and Brigham and Women’s Hospital (D.E.H., J.A.L., J.L.), Boston, Mass.

Correspondence to Dr Kenneth Walsh, PhD, Molecular Cardiology/Whitaker Cardiovascular Institute, Boston University School of Medicine, 715 Albany St, W611, Boston, Massachusetts 02118. E-mail kxwalsh{at}bu.edu

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.

Key Words: glutathione peroxidase-1 • hindlimb ischemia • endothelial progenitor cells • angiogenesis

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