Engineered Zinc Finger Protein–Mediated VEGF-A Activation Restores Deficient VEGF-A in Sensory Neurons in Experimental Diabetes


OBJECTIVE The objectives of the study were to evaluate retrograde axonal transport of vascular endothelial growth factor A (VEGF-A) protein to sensory neurons after 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 were assessed. RESULTS VEGF-A immunoreactivity (IR) was detected in small- to medium-diameter neurons in DRG of control rats. Fewer VEGF-A-IR neurons were observed in DRG from STZ-induced 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 h after 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 h that was sustained for 1 week after injection. VZ+434 protected against mechanical allodynia 8 weeks after STZ injection. CONCLUSIONS Intramuscular administration of VZ+434 increases VEGF-A protein levels in L4/5 DRG, correcting the deficit observed after 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.

DOI: 10.2337/db08-1526

Extracted Key Phrases

8 Figures and Tables

Citations per Year

113 Citations

Semantic Scholar estimates that this publication has 113 citations based on the available data.

See our FAQ for additional information.

Cite this paper

@inproceedings{Pawson2010EngineeredZF, title={Engineered Zinc Finger Protein–Mediated VEGF-A Activation Restores Deficient VEGF-A in Sensory Neurons in Experimental Diabetes}, author={Elizabeth J. Pawson and Beatriz Duran-Jimenez and Richard T Surosky and Heather E. Brooke and Sharon Kaye Spratt and David Richard Tomlinson and Natalie J Gardiner}, booktitle={Diabetes}, year={2010} }