Ablation of VEGFA following a lumbar intervertebral disc injury attenuates intradiscal neurovascular features and prevents chronic low back pain symptoms.
Overview
abstract
There are currently no therapies for the staggering disability and public health costs of chronic low back pain (LBP). Innervation of the degenerating intervertebral disc (IVD) is suspected to cause discogenic LBP, but the mechanisms that orchestrate the IVD's neo-innervation and subsequent symptoms of LBP remain unknown. We hypothesize that Vascular Endothelial Growth Factor-A (VEGFA) critically mediates the neurite invasion in the IVD and contributes to prolonged LBP. Initiating IVD degeneration through a mechanical injury, we evaluated the progression of neurovascular features into the IVD, as well as resultant LBP symptoms and locomotive performance at acute (3-weeks) and prolonged (12-weeks) time points following the IVD injury. To determine the role of VEGFA, we used a mouse model with ubiquitously inducible recombination of the floxed Vegfa allele (UBC-CreERT2; Vegfafl/f. The ablation of VEGFA attenuated the neurite and vessel infiltration into the degenerating IVD, and the VEGFA-null animals exhibited alleviated mechanical allodynia and improved locomotive performance. To determine the effects of IVD-derived VEGFA on endothelial cells and neurons, we cultured HMEC-1 endothelial cells and SH-SY5Y neurons using conditioned media from VEGFA-silenced (siRNA) human primary IVD cells stimulated by IL1β. The endothelial cells and neurons exposed to the secretome of the VEGFA-silenced IVD cells exhibited reduced growth, suggesting that the inhibition of IVD-derived VEGFA may be sufficient to attenuate intradiscal neurovascular features. Together, we show that VEGFA orchestrates the growth of intradiscal vessels and neurites that cause low back pain and impaired function, and the inhibition of VEGFA prevents prolonged sensitivity and motor impairment associated with discogenic low back pain.
