Regulation of alternative VEGF-A mRNA splicing is a therapeutic target for analgesia

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-A(165)a and VEGF-A(165)b (both contain 165 amino acids), both of which are neuroprotective. Under pathological conditions, such as in inflammation and cancer, the pro-angiogenic VEGF-A(165)a is upregulated and predominates over the VEGF-A(165)b isoform.

We show here that in rats and mice VEGF-A(165)a and VEGF-A(165)b have opposing effects on pain, and that blocking the proximal splicing event - leading to the preferential expression of VEGF-A(165)b over VEGF(165)a - prevents pain in vivo. VEGF-A(165)a sensitizes peripheral nociceptive neurons through actions on VEGFR2 and a TRPV1-dependent mechanism, thus enhancing nociceptive signaling. VEGF-A(165)b blocks the effect of VEGF-A(165)a. After nerve injury, the endogenous balance of VEGF-A isoforms switches to greater expression of VEGF-A(xxx)a compared to VEGF-A(xxx)b, through an SRPK1-dependent pre-mRNA splicing mechanism. Pharmacological inhibition of SRPK1 after traumatic nerve injury selectively reduced VEGF-A(xxx)a expression and reversed associated neuropathic pain. Exogenous VEGF-A(165)b 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-A(xxx)a/VEGF-A(xxx)b balance by targeting alternative RNA splicing may be a new analgesic strategy. (C) 2014 University of Nottingham. Published by Elsevier Inc.