Abstract

Objective: To evaluate retrograde axonal transport of VEGF-A protein to sensory neurons following intramuscular administration of an engineered zinc finger protein activator of endogenous VEGF-A (VZ+434) in an experimental model of diabetes, and to characterize the VEGF-A target neurons.

Research Design and Methods: We compared the expression of VEGF-A in lumbar (L)4/5 dorsal root ganglia (DRG) of control rats and VZ+434 treated and untreated streptozotocin (STZ)-induced diabetic rats. In addition, axonal transport of VEGF-A, activation of signal transduction pathways in the DRG, and mechanical sensitivity was assessed.

Results: VEGF-A-immunoreactivity (-IR) was detected in small-medium diameter neurons in DRG of control rats. Fewer VEGF-A-IR neurons were observed in DRG from STZ-diabetic rats, this decrease was confirmed and quantified by Western blotting. VZ+434 administration resulted in a significant increase in VEGF-A protein expression in ipsilateral DRG, 24 hours following injection. VEGF-A was axonally transported to the DRG via the sciatic nerve. VZ+434 administration resulted in significant activation of AKT in the ipsilateral DRG by 48 hours which was sustained for 1 week post-injection. VZ+434 protected against mechanical allodynia 8 weeks post-STZ.

Conclusions: Intramuscular administration of VZ+434 increases VEGF-A protein levels in L4/5 DRG correcting the deficit observed following induction of diabetes and protects against mechanical allodynia. Elevated VEGF-A levels result from retrograde axonal transport and are associated with altered signal transduction, via the phosphatidylinositol 3′-kinase pathway. These data support a neuroprotective role for VEGF-A in the therapeutic actions of VZ+434 and suggest a mechanism by which VEGF-A exerts this activity.