Vascular Endothelial Growth Factor and Spinal Cord Injury Pain

Abstract

Vascular endothelial growth factor (VEGF)-A mRNA was previously identified as one of the significantly upregulated transcripts in spinal cord injured tissue from adult rats that developed allodynia. To characterize the role of VEGF-A in the development of pain in spinal cord injury (SCI), we analyzed mechanical allodynia in SCI rats that were treated with either vehicle, VEGF-A isoform 165 (VEGF 165 ), or neutralizing VEGF 165 -specific antibody. We have observed that exogenous administration of VEGF 165 increased both the number of SCI rats that develop persistent mechanical allodynia, and the level of hypersensitivity to mechanical stimuli. Our analysis identified excessive and aberrant growth of myelinated axons in dorsal horns and dorsal columns of chronically injured spinal cords as possible mechanisms for both SCI pain and VEGF 165 -induced amplification of SCI pain, suggesting that elevated endogenous VEGF 165 may have a role in the development of allodynia after SCI. However, the neutralizing VEGF 165 antibody showed no effect on allodynia or axonal sprouting after SCI. It is possible that another endogenous VEGF isoform activates the same signaling pathway as the exogenouslyadministered 165 isoform and contributes to SCI pain. Our transcriptional analysis revealed that endogenous VEGF 188 is likely to be the isoform involved in the development of allodynia after SCI. To the best of our knowledge, this is the first study to suggest a possible link between VEGF, nonspecific sprouting of myelinated axons, and mechanical allodynia following SCI.

RETRACTED ARTICLE: Analyzing time-series microarray data reveals key genes in spinal cord injury

“…VEGFA is a glycosylated mitogen that specifically acts on endothelial cells and it can induce angiogenesis and inhibit apoptosis. Its mRNA level is significantly up-regulated in SCI [25]. Liu et al [26] elevated the level of VEGFA using an engineered transcription factor to enhance function recovery.…”

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

“…In this study we aimed to investigate the development of thermal and mechanical allodynia in AdV-ZFP-VEGF treated animals: hopeful that we would observe no increases in pain unlike the recent report by Nesic et al [31]. Animals were tested for pain at 4 and 8 weeks following SCI, and here we observe that animals receiving AdV-ZFP-VEGF gene therapy have a significant reduction in allodynia, for both at-level and below-level pain, at 8 weeks post-injury (Figure 10).…”

SRPK1 inhibition in vivo: modulation of VEGF splicing and potential treatment for multiple diseases

“…In SRPIN340-treated eyes a splicing switch was observed favouring production of anti-angiogenic VEGF xxx b isoforms Furthermore, SRPIN340 has demonstrated significant CNV suppression when administered daily as a topical eye drop, without any observed adverse effects to the cornea. SRPIN340-mediated inhibition of SRPK1 not only maintains the production of cytoprotective VEGF xxx b isoforms [42] but was also not toxic to cells even at concentrations as high as 5 mg/ml [14]. This treatment could be an alternative therapy to anti-VEGF-A intraocular injections in patients with exudative AMD, and it may be possible to extend this to diabetic proliferative retinopathy.…”

“…VEGF has been implicated in nociception, as administration of VEGF 165 results in hyperalgesia and allodynia [42], and abolition of VEGF signalling attenuates neuropathic pain [39] indicating that elevated VEGF contributes to neuropathic pain. The anti-VEGF and VEGF receptor blockade therapies used in the treatment of many diseases, as discussed above, are reported to result in non-desirable side effects, particularly the development of pain.…”