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Facchiano, F. et al.

Facchiano, D'Arcangelo, Russo, Fogliano, Mennella, Ragone, Zambruno, Carbone, Ribatti, Peschle, Capogrossi, Facchiano,

Glycated Fibroblast Growth Factor-2 Is Quickly Produced in Vitro upon Low-Millimolar Glucose Treatment and Detected in Vivo in Diabetic Mice.

Angiogenesis impairment in hyperglycemic patients represents a leading cause of severe vascular complications of both type-1 and -2 diabetes mellitus (DM). Angiogenesis dysfunction in DM is related to glycemic control; however, molecular mechanisms involved are still unclear. Fibroblast growth factor-2 ( FGF-2) is a potent angiogenic factor and, according to previous evidence, may represent a key target of molecular modifications triggered by high-sugar exposure. Therefore, the purpose of this study was to investigate whether short incubation with hyperglycemic levels of glucose affected FGF-2 and whether glucose-modified FGF-2 was detectable in vivo. Biochemical analyses carried out with SDS-PAGE, fluorescence emission, mass-spectrometry, immunoblot, and competitive ELISA experiments demonstrated that human FGF-2 undergoes a rapid and specific glycation upon 12.5-50 mm glucose exposure. In addition, FGF-2 exposed for 30 min to 12.5 mm glucose lost mitogenic and chemotactic activity in a time- and dose-dependent manner. Under similar conditions, binding affinity to FGF receptor 1 was dramatically reduced by 20-fold, as well as FGF receptor 1 and ERK-1/2 phosphorylation, and FGF-2 lost about 45% of angiogenic activity in two different in vivo angiogenic (Matrigel and chorioallantoic-membrane) assays. Such glucose-induced modification was specific, because other angiogenic growth factors, namely platelet-derived growth factor BB and placental-derived growth factor were not significantly or markedly less modified. Finally, for the first time, glycated- FGF-2 was detected in vivo, in tissues from hyperglycemic nonobese diabetic mice, in significantly higher amounts than in normoglycemic mice. In conclusion, hyperglycemic levels of glucose may strongly affect FGF-2 structure and impair its angiogenic features, and endogenous glycated- FGF-2 is present in diabetic mice, indicating a novel pathogenetic mechanism underlying angiogenesis defects in DM.[1]

References

Glycated Fibroblast Growth Factor-2 Is Quickly Produced in Vitro upon Low-Millimolar Glucose Treatment and Detected in Vivo in Diabetic Mice. Facchiano, F., D'Arcangelo, D., Russo, K., Fogliano, V., Mennella, C., Ragone, R., Zambruno, G., Carbone, V., Ribatti, D., Peschle, C., Capogrossi, M.C., Facchiano, A. Mol. Endocrinol. (2006) [Pubmed]

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