Engineered Zinc Finger Protein-mediated VEGF-a Activation Restores Deficient VEGF-a in Sensory Neurons in Experimental Diabetes

Overview

Journal Diabetes

Specialty Endocrinology

Date 2009 Nov 26

PMID 19934008

Citations 9

Authors

Elizabeth J Pawson

Beatriz Duran-Jimenez

Richard Surosky

Heather E Brooke

S Kaye Spratt

David R Tomlinson

Natalie J Gardiner

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

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Cisplatin induced sensory neuropathy is prevented by vascular endothelial growth factor-A.

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