Placental growth factor-2 gene transfer by electroporation restores diabetic sensory neuropathy in mice

Placental growth factor-2 (PlGF-2) exhibits neurotrophic activity in dorsal root ganglion (DRG) neurons through the neuropilin-1 (NP-1) receptor in vitro. To examine the potential utility of PlGF-2 therapy for treating diabetic neuropathy, we performed intramuscular PlGF-2 gene transfer by electroporation, and examined its effects on sensory neuropathy in diabetic mice. PlGF-2 was overexpressed in the tibial anterior (TA) muscles of streptozotocin-induced diabetic mice with hypoalgesia using a PlGF-2 plasmid injection with electroporation. The nociceptive threshold was measured using a paw-pressure test. In addition, we overexpressed PlGF-1, an isoform of PlGF that does not bind NP-1. The sciatic nerve and skin were examined 3weeks after PlGF-2 electro-gene transfer. The overexpression and secretion of PlGF-2 in TA muscles were confirmed by an increase in PlGF levels in TA muscles and plasma, and strongly PlGF positive myofibers in TA muscles. Two weeks after electro-gene transfer into the bilateral TA muscles, the previously elevated nociceptive threshold was found to be significantly decreased in all treated mice. PlGF-1 gene transfer by electroporation did not significantly decrease the nociceptive threshold in diabetic mice. No increase in the number of endoneurial vessels in the sciatic nerve was found in the PlGF-2 plasmid-electroporated mice. A reduction of area of immunoreactivity in epidermal nerves in diabetic mice was restored by PlGF-2 gene transfer. These findings suggest that PlGF-2 electro-gene therapy can significantly ameliorate sensory deficits (i.e. hypoalgesia) in diabetic mice through NP-1 in DRG and peripheral nerves.