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Abstract

Endothelial cells and their metabolic state regulate glucose transport into underlying tissues. Here, we show that low oxygen tension stimulates human umbilical vein endothelial cell 18F-fluorodeoxyglucose (18F-FDG) uptake and lactate production. This was accompanied by augmented hexokinase activity and membrane Glut-1, and increased accumulation of hypoxia-inducible factor-1α (HIF1α). Restoration of oxygen reversed the metabolic effect, but this was blocked by HIF1α stabilization. Hypoxia-stimulated 18F-FDG uptake was completely abrogated by silencing of HIF1α expression or by a specific inhibitor. There was a rapid and marked increase of reactive oxygen species (ROS) by hypoxia, and ROS scavenging or NADPH oxidase inhibition completely abolished hypoxia-stimulated HIF1α and 18F-FDG accumulation, placing ROS production upstream of HIF1α signaling. Hypoxia-stimulated HIF1α and 18F-FDG accumulation was blocked by the protein kinase C (PKC) inhibitor, staurosporine. The phosphatidylinositol 3-kinase (PI3K) inhibitor, wortmannin, blocked hypoxia-stimulated 18F-FDG uptake and attenuated hypoxia-responsive element binding of HIF1α without influencing its accumulation. Thus, ROS-driven HIF1α accumulation, along with PKC and PI3K signaling, play a key role in triggering accelerated glycolysis in endothelial cells under hypoxia, thereby contributing to 18F-FDG transport.

Author information​

Paik JY1, Jung KH2, Lee JH2, Park JW2, Lee KH3.

1Department of Nuclear Medicine, Samsung Medical Center, Seoul, Republic of Korea.

2Department of Nuclear Medicine, Samsung Medical Center, Seoul, Republic of Korea; Samsung Advanced Institute for Health Sciences & Technology, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.

3Department of Nuclear Medicine, Samsung Medical Center, Seoul, Republic of Korea; Samsung Advanced Institute for Health Sciences & Technology, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea. Electronic address: khnm.lee@samsung.com.