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Sugar-induced modification of fibroblast growth factor 2 reduces its angiogenic activity in vivo
Francesco Facchiano1, Alessandro Lentini, Vincenzo Fogliano
1Laboratorio di Patologia Vascolare, Istituto Dermopatico dell'Immacolata, Roma, Italy. f.facchiano@idi.it
Abstract:
Both clinical and animal studies have shown that angiogenesis is impaired in diabetes mellitus; however, the mechanisms responsible for this effect are poorly characterized. The major aims of the present study were to evaluate the effect of hyperglycemia on fibroblast growth factor 2 (FGF2)-induced angiogenesis in vivo and to determine whether FGF2 non-enzymatic glycation occurs in hyperglycemic mice. New blood vessel formation was examined in reconstituted basement membrane protein (Matrigel) plugs containing FGF2 in control normoglycemic CD1 and in hyperglycemic nonobese diabetic (NOD) mice. FGF2-induced angiogenesis in NOD mice was inhibited by 75% versus control mice (P < 0.001). When recombinant FGF2 was mixed with Matrigel and injected in mice, it was found that recombinant FGF2 glycation was significantly enhanced in plugs from NOD versus control mice (P < 0.01). In the Boyden chamber assay, the chemotactic effect of glycated FGF2 toward endothelial cells was lower than that of unmodified FGF2 (P < 0.01). Further, FGF2 glycated in vitro and co-injected with Matrigel in CD1 mice was a weaker angiogenic stimulus than unglycated FGF2 (P < 0.005). These results indicate that FGF2-induced angiogenesis is inhibited in diabetic mice, FGF2 glycation is enhanced in hyperglycemic mice, and glycation markedly reduces FGF2 chemotactic effect in vitro and its angiogenic properties in vivo. Thus, FGF2 glycation may represent a mechanism responsible for the impairment of angiogenesis in diabetes mellitus.
Insights
Hyperglycemia impairs blood vessel formation (angiogenesis) in diabetes by causing fibroblast growth factor 2 (FGF2) to become glycated, reducing its effectiveness. This glycation is a key mechanism behind impaired angiogenesis in diabetes mellitus.
Area of Science:
- Biomedical research
- Endocrinology
- Vascular biology
Background:
- Impaired angiogenesis is a known complication of diabetes mellitus.
- The precise mechanisms underlying this impairment remain poorly understood.
- Fibroblast growth factor 2 (FGF2) plays a crucial role in angiogenesis.
Purpose of the Study:
- To investigate the impact of hyperglycemia on FGF2-induced angiogenesis in vivo.
- To determine if FGF2 undergoes non-enzymatic glycation in hyperglycemic conditions.
- To elucidate the role of FGF2 glycation in diabetes-related angiogenesis dysfunction.
Main Methods:
- Angiogenesis was assessed using Matrigel plugs containing FGF2 in normoglycemic and hyperglycemic (nonobese diabetic, NOD) mice.
- Recombinant FGF2 glycation levels were measured in Matrigel plugs from both mouse models.
- The chemotactic activity of glycated versus unglycated FGF2 on endothelial cells was evaluated using a Boyden chamber assay.
- The angiogenic potential of in vitro glycated FGF2 was tested in normoglycemic mice.
Main Results:
- FGF2-induced angiogenesis was significantly inhibited (75%) in hyperglycemic NOD mice compared to controls.
- Non-enzymatic glycation of FGF2 was significantly enhanced in Matrigel plugs from NOD mice.
- Glycated FGF2 exhibited reduced chemotactic effects on endothelial cells and weaker angiogenic properties in vivo.
- In vitro glycation of FGF2 diminished its angiogenic stimulus.
Conclusions:
- Hyperglycemia in diabetes mellitus inhibits FGF2-driven angiogenesis.
- FGF2 glycation is increased in hyperglycemic mice and reduces its biological activity.
- FGF2 glycation is identified as a potential mechanism contributing to impaired angiogenesis in diabetes mellitus.