Abstract
Vascular endothelial growth factor-A (VEGF-A) is best known as a key regulator of the formation of new blood vessels. Neutralization of VEGF-A with anti-VEGF therapy e.g. bevacizumab, can be painful, and this is hypothesized to result from a loss of VEGF-A-mediated neuroprotection. The multiple vegf-a gene products consist of two alternatively spliced families, typified by VEGF-A165a and VEGF-A165b (both contain 165 amino acids), both of which are neuroprotective. Under pathological conditions, such as in inflammation and cancer, the pro-angiogenic VEGF-A165a is upregulated and predominates over the VEGF-A165b isoform.We show here that in rats and mice VEGF-A165a and VEGF-A165b have opposing effects on pain, and that blocking the proximal splicing event – leading to the preferential expression of VEGF-A165b over VEGF165a – prevents pain in vivo. VEGF-A165a sensitizes peripheral nociceptive neurons through actions on VEGFR2 and a TRPV1-dependent mechanism, thus enhancing nociceptive signaling. VEGF-A165b blocks the effect of VEGF-A165a.After nerve injury, the endogenous balance of VEGF-A isoforms switches to greater expression of VEGF-Axxxa compared to VEGF-Axxxb, through an SRPK1-dependent pre-mRNA splicing mechanism. Pharmacological inhibition of SRPK1 after traumatic nerve injury selectively reduced VEGF-Axxxa expression and reversed associated neuropathic pain. Exogenous VEGF-A165b also ameliorated neuropathic pain.We conclude that the relative levels of alternatively spliced VEGF-A isoforms are critical for pain modulation under both normal conditions and in sensory neuropathy. Altering VEGF-Axxxa/VEGF-Axxxb balance by targeting alternative RNA splicing may be a new analgesic strategy.
Highlights
Inhibition of Vascular endothelial growth factor-A (VEGF-A) action with anti-VEGF-A therapies, e.g. bevacizumab or VEGF-A receptor inhibitors results in pain, when given alone (Burger et al, 2007; Cohen and Hochster, 2007) or in combination with chemotherapies (Cohen et al, 2007; Miller et al, 2007; Garcia et al, 2008; Langenberg et al, 2011 )
A contributes to pain are supported by observations that inhibition of VEGF receptor 2 (VEGFR2) exacerbates peripheral neuronal damage, which is often associated with pain
Clinical and experimental reports of the detrimental effects of anti-VEGF agents on neuronal integrity and pain have raised concerns over the use of such therapies as their use can result in neuronal damage, often leading to pain (Verheyen et al, 2012)
Summary
Inhibition of VEGF-A action with anti-VEGF-A therapies, e.g. bevacizumab or VEGF-A receptor inhibitors (e.g., vandetanib) results in pain, when given alone (Burger et al, 2007; Cohen and Hochster, 2007) or in combination with chemotherapies (Cohen et al, 2007; Miller et al, 2007; Garcia et al, 2008; Langenberg et al, 2011 ). A contributes to pain are supported by observations that inhibition of VEGF receptor 2. A165b (Harper and Bates, 2008) Both families have sister isoforms of the same length so they are referred collectively as VEGF-Axxxa and VEGF-Axxxb; xxx represents the number of amino acids. The isoform families differ only in their six C terminal amino acids They are both capable of binding to VEGFR2 with similar affinities, but the functional results of receptor activation are multivariate (Table 1) (Ballmer-Hofer et al., 2011). Control of relative isoform expression occurs by alternative pre-mRNA splicing of either proximal or distal splice sites in exon 8 (Fig. 1)
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