Glycated fibroblast growth factor-2 is quickly produced in vitro upon low-millimolar glucose treatment and detected in vivo in diabetic mice

Francesco Facchiano*, Daniela D'Arcangelo, Katia Russo, Vincenzo Fogliano, Carmela Mennella, Raffaele Ragone, Giovanna Zambruno, Virginia Carbone, Domenico Ribatti, Cesare Peschle, Maurizio C. Capogrossi, Antonio Facchiano

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

17 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)2806-2818
Number of pages13
JournalMolecular endocrinology
Volume20
Issue number11
DOIs
Publication statusPublished - 1 Nov 2006
Externally publishedYes

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    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. (2006). Glycated fibroblast growth factor-2 is quickly produced in vitro upon low-millimolar glucose treatment and detected in vivo in diabetic mice. Molecular endocrinology, 20(11), 2806-2818. https://doi.org/10.1210/me.2005-0322