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Nitric Oxide Stimulates ¹⁸F-FDG Uptake in Human Endothelial Cells Through Increased Hexokinase Activity and GLUT1 Expression

Department of Nuclear Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

The endothelium constitutes a functionally active organ critically involved in angiogenesis. Nitric oxide (NO) is an important regulator of vascular homeostasis and angiogenesis and stimulates glucose metabolism in certain cells. We thus investigated the effect of exogenous NO on ¹⁸F-FDG transport in human endothelial cells. Methods: Human umbilical vein endothelial cells (HUVECs) were treated with the NO donors sodium nitroprusside (SNP) or diethylenetriamine (DETA), in concentrations of 1 µmol/L–1 mmol/L for up to 24 h. ¹⁸F-FDG uptake levels corrected for protein content were determined by cellular radioactivity measured after 30-min incubation. Cells were evaluated for total hexokinase activity and plasma membrane glucose transporter 1 (GLUT1) levels, and involvement of potential signaling pathways was investigated by cotreatment with respective protein kinase inhibitors. Results: Both SNP and DETA stimulated HUVEC ¹⁸F-FDG uptake, which began at 16 h and peaked at 24 h. The increase in ¹⁸F-FDG uptake was dose dependent, reaching 464.0% ± 49.8% and 254.5% ± 10.8% of control levels at 24 h with 1 mmol/L SNP and DETA, respectively. Exposure of HUVECs to 1 mmol/L SNP resulted in a 3.5 ± 0.3-fold elevation in hexokinase activity (P < 0.01) and a significant increase in GLUT1 levels. SNP-stimulated ¹⁸F-FDG uptake was abolished by cotreatment with cycloheximide, the tyrosine kinase inhibitor genistein, the phosphatidylinositol-3 kinase (PI3K) inhibitor wortmannin, or the protein kinase C inhibitor staurosporine. Conclusion: NO stimulates ¹⁸F-FDG uptake in HUVECs through an increase in GLUT1 expression and hexokinase activity, which appears to involve both protein kinase C and PI3K pathways.

Key Words: human endothelial cells • hexokinase activity • glucose transporter • ¹⁸F-FDG uptake • nitrous oxide

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