Abstract
The pathogenetic role of vascular endothelial growth factor (VEGF) in long-term retinal and kidney complications of diabetes has been demonstrated. Conversely, little is known in diabetic neuropathy. We examined the modulation of VEGF pathway at mRNA and protein level on dorsal root ganglion (DRG) neurons and Schwann cells (SC) induced by hyperglycaemia. Moreover, we studied the effects of VEGF neutralization on hyperglycemic DRG neurons and streptozotocin-induced diabetic neuropathy. Our findings demonstrated that DRG neurons were not affected by the direct exposition to hyperglycaemia, whereas showed an impairment of neurite outgrowth ability when exposed to the medium of SC cultured in hyperglycaemia. This was mediated by an altered regulation of VEGF and FLT-1 receptors. Hyperglycaemia increased VEGF and FLT-1 mRNA without changing their intracellular protein levels in DRG neurons, decreased intracellular and secreted protein levels without changing mRNA level in SC, while reduced the expression of the soluble receptor sFLT-1 both in DRG neurons and SC. Bevacizumab, a molecule that inhibits VEGF activity preventing the interaction with its receptors, restored neurite outgrowth and normalized FLT-1 mRNA and protein levels in co-cultures. In diabetic rats, it both prevented and restored nerve conduction velocity and nociceptive thresholds. We demonstrated that hyperglycaemia early affected neurite outgrowth through the impairment of SC-derived VEGF/FLT-1 signaling and that the neutralization of SC-secreted VEGF was protective both in vitro and in vivo models of diabetic neuropathy.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Angiogenesis Inhibitors / pharmacology*
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Animals
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Antibodies, Monoclonal, Humanized / pharmacology*
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Bevacizumab
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Coculture Techniques
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Diabetes Mellitus, Experimental / chemically induced
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Diabetes Mellitus, Experimental / drug therapy*
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Diabetes Mellitus, Experimental / genetics
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Diabetes Mellitus, Experimental / pathology
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Diabetic Neuropathies / chemically induced
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Diabetic Neuropathies / drug therapy*
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Diabetic Neuropathies / genetics
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Diabetic Neuropathies / pathology
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Ganglia, Spinal / drug effects
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Ganglia, Spinal / metabolism
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Ganglia, Spinal / pathology
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Gene Expression Regulation
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Hyperglycemia / chemically induced
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Hyperglycemia / drug therapy*
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Hyperglycemia / genetics
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Hyperglycemia / pathology
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Male
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Neural Conduction / drug effects
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Neurites / drug effects
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Neurites / metabolism
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Neurites / pathology
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Nociception / drug effects
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Rats
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Rats, Sprague-Dawley
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Schwann Cells / drug effects*
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Schwann Cells / metabolism
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Schwann Cells / pathology
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Sensory Receptor Cells / drug effects
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Sensory Receptor Cells / metabolism
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Sensory Receptor Cells / pathology
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Signal Transduction
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Streptozocin
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Vascular Endothelial Growth Factor A / antagonists & inhibitors*
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Vascular Endothelial Growth Factor A / genetics
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Vascular Endothelial Growth Factor A / metabolism
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Vascular Endothelial Growth Factor Receptor-1 / genetics
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Vascular Endothelial Growth Factor Receptor-1 / metabolism
Substances
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Angiogenesis Inhibitors
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Antibodies, Monoclonal, Humanized
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Vascular Endothelial Growth Factor A
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vascular endothelial growth factor A, rat
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Bevacizumab
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Streptozocin
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Flt1 protein, rat
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Vascular Endothelial Growth Factor Receptor-1
Grants and funding
The study has been funded by the “Ricerca Corrente” of the Italian Ministry of Heath to the IRCCS Foundation, “Carlo Besta” Neurological Institute, Milan, Italy. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.