Hypoxia-inducible expression of vascular endothelial growth factor for the treatment of spinal cord injury in a rat model

Abstract

<jats:sec> <jats:title>Object</jats:title> <jats:p>Vascular endothelial growth factor (VEGF) has been investigated as a therapy for many disorders and injuries involving ischemia. In this report, we constructed and evaluated a hypoxia-inducible VEGF expression system as a treatment for spinal cord injury (SCI).</jats:p></jats:sec> <jats:sec> <jats:title>Methods</jats:title> <jats:p>The hypoxia-inducible VEGF plasmid was constructed using the erythropoietin (Epo) enhancer with the Simian virus 40 (SV40) promoter (pEpo-SV-VEGF) or the RTP801 promoter (pRTP801-VEGF). The expression of VEGF in vitro was evaluated after transfection into N2A cells. The plasmids were then injected into rat spinal cords with contusion injuries. The expression of VEGF in vivo was measured using reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay. Locomotor recovery in the rats was evaluated using the Basso, Beattie and Bresnahan (BBB) scale for locomotor analysis.</jats:p></jats:sec> <jats:sec> <jats:title>Results</jats:title> <jats:p>In vitro transfection showed that pEpo-SV-VEGF or pRTP801-VEGF induced VEGF expression under hypoxic conditions, whereas pSV-VEGF did not. The VEGF level was higher in the pEpo-SV-VEGF and pRTP801-VEGF groups than in the control group. The VEGF expression was detected in neurons and astrocytes of the spinal cord. Locomotor recovery was improved in the pEpo-SV-VEGF and pRTP801-VEGF groups, and BBB scores were higher than in the control group. Staining using terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate nick-end labeling showed that the number of apoptotic cells decreased in the plasmid-injected groups compared with the control group, and significant differences were observed between the hypoxia-responsive groups and the pSV-VEGF group.</jats:p></jats:sec> <jats:sec> <jats:title>Conclusions</jats:title> <jats:p>These results suggest that the hypoxia-inducible VEGF expression system may be useful for gene therapy of SCI.</jats:p></jats:sec>

Delayed Administration of a Bio-Engineered Zinc-Finger VEGF-A Gene Therapy Is Neuroprotective and Attenuates Allodynia Following Traumatic Spinal Cord Injury

“…Choi et al used a hypoxia-inducible VEGF-A expression system to treat rats with SCI and observed neuroprotective effects and enhanced VEGF-A expression [56]. Another group used an adenovirus coding for VEGF 165 , delivered via matrigel, in a partial spinal cord transection model.…”

Vascular Endothelial Growth Factor: Adaptive Changes in the Neuroglialvascular Unit

“…Studies carried out in traumatic spinal cord injury showed that expression of VEGF and its receptors is increased [82] and that local delivery of VEGF improves recovery [93]. These studies have demonstrated that whereas VEGFR-2 inhibition extends the hemorrhagic area [93] and increases neuronal and glial injury markers [82], VEGF plasmid administration improves the outcome of this lesion [94]. Nonetheless, the permeability effects of VEGF could offset potential beneficial effects in stroke and other ischemic disorders.…”

Integrated transcriptomic response to cardiac chronic hypoxia: translation regulators and response to stress in cell survival

“…Although there is practically no statistical significance of this finding because we compared only two males with two females at each time point and treatment, the robustness and similarity with the results obtained for the hypoxic kidneys makes it interesting. This observation of gender dependence of gene expression regulation could be important when designing therapies (e.g., Choi et al 2007) or targeting hypoxic cells in tumors (e.g., Sovik et al 2007;Post et al 2007). …”