Favorable effect of VEGF gene transfer on ischemic peripheral neuropathy

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.

Local transplantation of human multipotent adipose-derived stem cells accelerates fracture healing via enhanced osteogenesis and angiogenesis

“…The migration activity was evaluated with a modified Boyden's chamber assay as described previously. 30 hMADS cells (5 Â 10 4 cells per well) were seeded onto upper chambers in 24-well Transwell culture plates (Corning Incorporated Life Science, MA, USA) and lower chambers were filled with DMEM with 10% FBS containing BMP-2 or VEGF (0, 5, 10, 50 or 100 ng/ml) followed by incubation for 6 h at 371C in 5% CO 2 . Migrated cells were stained with DAPI and counted in four high-power fields ( Â 200) per chamber under a fluorescent microscope and averaged.…”

VEGF: a critical player in neurodegeneration

“…VEGF also augmented vascularization and reduced retrograde degeneration of transected corticospinal tract axons, and, remarkably, VEGF stimulated some axons to regenerate across the injured area (39). Intramuscular VEGF gene transfer prevented axonal loss and myelin degeneration and preserved nerve conduction velocities and normal sensory nerve action potentials in a rabbit model of ischemic neuropathy (24) and in patients with critical hind limb ischemia (40). This favorable effect of VEGF was attributed to a vascular effect (i.e., restoration of neural blood flow), as well as to a direct effect on Schwann cells (24).…”

“…Furthermore, under conditions of hypoxic, excitotoxic, or oxidative stress, VEGF increases the survival of hippocampal, cortical, cerebellar granule, dopaminergic, autonomic, and sensory neurons (2,14,(16)(17)(18)(20)(21)(22)(23). VEGF also stimulates the growth (14) and survival of Schwann cells in hypoxic conditions (24), and increases proliferation and migration of astrocytes (23,25) and microglial cells (26). Future genetic and functional studies in vivo will have to elucidate how important the neuroprotective effect of VEGF is in the pathogenesis of other neurodegenerative disorders.…”

“…Intramuscular VEGF gene transfer prevented axonal loss and myelin degeneration and preserved nerve conduction velocities and normal sensory nerve action potentials in a rabbit model of ischemic neuropathy (24) and in patients with critical hind limb ischemia (40). This favorable effect of VEGF was attributed to a vascular effect (i.e., restoration of neural blood flow), as well as to a direct effect on Schwann cells (24). VEGF gene transfer also preserved neural flow by preventing regression of the vasa nervorum, resulting in restoration of peripheral nerve function in rats with streptozotocin-induced diabetes (41).…”

Suppression of cutaneous inflammation by intradermal gene delivery

“…Several functional genes have been expressed in the skin for therapeutic application using this simple but elegant technique. [9][10][11] For example, injection of IL-8 encoding plasmid into the skin induced neutrophil recruitment. 12 Similarly, IL-6 and IL-10 gene expression was demonstrated in the skin following gene transfer.…”