Fibronectin stimulates endothelial cell 18F-FDG uptake through focal adhesion kinase-mediated phosphatidylinositol 3-kinase/Akt signaling.
There has been recent interest in the relationship between (18)F-FDG uptake and the angiogenic activity of endothelial cells (ECs). The angiogenic process is strongly dependent on the interaction of ECs with matrix fibronectin (FN), a key regulator of EC survival, migration, and proliferation. Therefore, we investigated how FN influences EC glucose uptake and elucidated the signaling pathways that mediate this effect.


METHODS
Human umbilical vein ECs were allowed to adhere to FN-coated plates and were compared with control cells for (18)F-FDG uptake, membrane GLUT1 levels, and hexokinase activity. The roles of focal adhesion kinase (FAK), phosphatidylinositol 3-kinase (PI3K), and Akt were evaluated with Western blotting, small interfering RNA (siRNA), and specific inhibitors.


RESULTS
FN adhesion significantly enhanced the protein-corrected (18)F-FDG uptake in HUVEC, to 2.1-, 2.7-, and 4.3-fold that in control cells by 2, 3, and 5 d, respectively. This effect was mediated by the upregulation of both membrane GLUT1 expression and hexokinase activity and was accompanied by FAK activation. Silencing of FAK signaling by siRNA completely abrogated both FN-induced FAK phosphorylation and (18)F-FDG uptake. FN also activated PI3K and Akt, well-known angiogenesis mediators, and the inhibition of either pathway totally abolished the effect of FN on (18)F-FDG uptake. Nitric oxide, a downstream Akt effector that stimulates glucose uptake, was not involved in the metabolic effect of FN.


CONCLUSIONS
The results of this study demonstrated that an EC-FN interaction induces strong enhancement of (18)F-FDG uptake through the upregulation of GLUT1 expression and hexokinase activity. The findings also showed that the response occurs through FAK-mediated activation of PI3K and Akt, indicating a role for this pathway in modulating EC glucose metabolism.
Paik
Jin-Young
JY
Department of Nuclear Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. khleenm@yahoo.co.kr
Ko
Bong-Ho
BH
Jung
Kyung-Ho
KH
Lee
Kyung-Han
KH
D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D005353:Fibronectins / Q000008:administration & dosage*; D019788:Fluorodeoxyglucose F18 / Q000493:pharmacokinetics*; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism*; D006801:Humans; D008657:Metabolic Clearance Rate / Q000187:drug effects; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
D005353:Fibronectins; D019275:Radiopharmaceuticals; D019788:Fluorodeoxyglucose F18; D019869:Phosphatidylinositol 3-Kinases; D051416:Focal Adhesion Protein-Tyrosine Kinases; D051057:Proto-Oncogene Proteins c-akt