Impaired angiogenesis in glutathione peroxidase-1-deficient mice is associated with endothelial progenitor cell dysfunction
Impaired angiogenesis in glutathione peroxidase-1-deficient mice is associated with endothelial progenitor cell dysfunction
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DOI：
10.1161/01.res.0000200740.57764.52
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发表时间：
2006-02-03
影响因子：
20.1
通讯作者：
Walsh, K
中科院分区：
文献类型：
--
作者：
Galasso, G;Schiekofer, S;Walsh, K
几种血管疾病的特征是活性氧 (ROS) 水平升高。通过表达 1 型谷胱甘肽过氧化物酶 (GPx-1) 等酶，保护血管内皮免受氧化应激。在这项研究中，我们在 GPx-1 纯合缺陷小鼠模型中研究了血管氧化应激对缺血诱导的新血管形成的影响。根据激光多普勒测量内收肌血流量和毛细血管密度，GPx-1 缺陷小鼠在后肢缺血手术后表现出血运重建受损。 GPx-1缺陷小鼠还表现出响应缺血性损伤或皮下注射血管内皮生长因子蛋白而增加内皮祖细胞（EPC）水平的能力受损。从 GPx-1 缺陷小鼠中分离的 EPC 在体外表现出中和氧化应激的能力降低，这与向血管内皮生长因子的迁移受损以及对 ROS 诱导的细胞凋亡的敏感性增加有关。从 GPx-1 缺陷型小鼠中分离的 EPC 在野生型小鼠中促进血管生成的能力受损，而野生型 EPC 可以有效刺激 GPx-1 缺陷型小鼠中的血管生成。这些数据表明，EPC 功能障碍是 ROS 水平升高导致血管疾病的一种机制。
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.