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

被引:17
作者
Pawson, Elizabeth J. [1 ]
Duran-Jimenez, Beatriz [1 ]
Surosky, Richard [2 ]
Brooke, Heather E. [1 ]
Spratt, S. Kaye [2 ]
Tomlinson, David R. [1 ]
Gardiner, Natalie J. [1 ]
机构
[1] Univ Manchester, Fac Life Sci, Manchester, Lancs, England
[2] Sangamo Biosci, Richmond, CA USA
基金
英国医学研究理事会;
关键词
ENDOTHELIAL GROWTH-FACTOR; DORSAL-ROOT GANGLIA; STIMULATES AXONAL OUTGROWTH; GENE-TRANSFER; MITOCHONDRIAL DYSFUNCTION; THERAPEUTIC ANGIOGENESIS; NEUROTROPHIC FACTOR; FACTOR EXPRESSION; PERIPHERAL-NERVE; FACTOR NGF;
D O I
10.2337/db08-1526
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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. Diabetes 59:509-518, 2010
引用
收藏
页码:509 / 518
页数:10
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