Abstract
Ischemic peripheral neuropathy is a frequent, irreversible complication of lower extremity vascular insufficiency. We investigated whether ischemic peripheral neuropathy could be prevented and/or reversed by gene transfer of an endothelial cell mitogen designed to promote therapeutic angiogenesis. Intramuscular gene transfer of naked DNA encoding vascular endothelial growth factor (VEGF) simultaneously with induction of hindlimb ischemia in rabbits abrogated the substantial decrease in motor and sensory nerve parameters, and nerve function recovered promptly. When gene transfer was administered 10 days after induction of ischemia, nerve function was restored earlier and/or recovered faster than in untreated rabbits. These findings are due in part to enhanced hindlimb perfusion. In addition, however, the demonstration of functional VEGF receptor expression by Schwann cells indicates a direct effect of VEGF on neural integrity as well. These findings thus constitute a new paradigm for the treatment of ischemic peripheral neuropathy.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Cell Movement / drug effects
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Cell Movement / physiology
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Cell Survival / drug effects
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Cells, Cultured
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Disease Models, Animal
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Endothelial Growth Factors / genetics*
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Endothelial Growth Factors / pharmacology
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Gene Transfer Techniques*
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Genetic Therapy*
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Hindlimb / innervation
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Hindlimb / metabolism
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Hindlimb / physiopathology
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Ischemia / therapy*
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Lymphokines / genetics*
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Lymphokines / pharmacology
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / metabolism
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Neuropilin-1
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Peripheral Nervous System / blood supply*
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Peripheral Nervous System Diseases / metabolism
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Peripheral Nervous System Diseases / therapy*
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism
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Rabbits
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Rats
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Rats, Sprague-Dawley
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Receptor Protein-Tyrosine Kinases / genetics
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Receptor Protein-Tyrosine Kinases / metabolism
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Receptors, Growth Factor / genetics
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Receptors, Growth Factor / metabolism
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Receptors, Vascular Endothelial Growth Factor
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Schwann Cells / drug effects
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Schwann Cells / physiology
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Vascular Endothelial Growth Factor A
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Vascular Endothelial Growth Factor Receptor-1
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Vascular Endothelial Growth Factors
Substances
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Endothelial Growth Factors
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Lymphokines
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Nerve Tissue Proteins
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Proto-Oncogene Proteins
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Receptors, Growth Factor
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Vascular Endothelial Growth Factor A
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Vascular Endothelial Growth Factors
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Neuropilin-1
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Receptor Protein-Tyrosine Kinases
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Receptors, Vascular Endothelial Growth Factor
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Vascular Endothelial Growth Factor Receptor-1