Vascular endothelial growth factor signaling in injured nerves underlies peripheral sensitization in neuropathic pain

• Published in: Journal of neurochemistry 2014-04, Vol.129 (1), p.169-178
• Main Authors: Kiguchi, Norikazu, Kobayashi, Yuka, Kadowaki, Yui, Fukazawa, Yohji, Saika, Fumihiro, Kishioka, Shiroh
• Format: Article
• Language: English
• Subjects: Angiogenesis; Animals; CXCR4; cytokine; epigenetics; Inflammatory diseases; Male; Mice; Mice, Inbred C57BL; Mice, Inbred ICR; Mice, Transgenic; Neuralgia - metabolism; Neuralgia - pathology; Neurochemistry; Pain; Peripheral Nerve Injuries - metabolism; Peripheral Nerve Injuries - pathology; Protein expression; sciatic nerve; Signal Transduction - physiology; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - biosynthesis
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/jnc.12614

Chronic neuroinflammation may be a critical component of intractable inflammatory diseases, including neuropathic pain. Because angiogenesis as a result of vascular endothelial growth factor (VEGF) signaling plays a pivotal role in inflammation, we focused on the mechanisms of VEGF‐regulated neuropathic pain in mice. The mRNA and protein expression of VEGFA were up‐regulated in the injured sciatic nerve after partial sciatic nerve ligation (PSL). VEGFA was localized to accumulated macrophages and neutrophils derived from bone marrow. Up‐regulation of VEGFA was mediated by histone H3 acetylation and trimethylation in its promoter region. VEGF receptors (VEGFR1 and VEGFR2) were localized to vascular endothelial cells or macrophages. By ex vivo fluorescence imaging and immunohistochemistry using DiI fluorescence, progression of angiogenesis was observed in the injured sciatic nerve after PSL. Perineural administration of pharmacological inhibitors of VEGFA and VEGFR tyrosine kinases prevented tactile allodynia and thermal hyperalgesia caused by PSL. Moreover, we determined the contribution of VEGF‐ and CXC‐chemokine receptor 4‐expressing angiogenic macrophages to neuropathic pain. Taken together, VEGFA is up‐regulated in injured peripheral nerves and participates in angiogenesis and prolonged pain behaviors through its receptors. We propose that VEGFA‐related components may underlie peripheral sensitization leading to neuropathic pain. Angiogenesis due to VEGF signaling is a key component of chronic inflammation. VEGFA up‐regulation and pathological angiogenesis were observed in the injured nerves in mice. Pharmacological inhibition of VEGF signaling suppressed neuropathic pain behaviors. Therefore, VEGFA‐related components may underlie peripheral neuroinflammation leading to neuropathic pain. Angiogenesis due to VEGF signaling is a key component of chronic inflammation. VEGFA up‐regulation and pathological angiogenesis were observed in the injured nerves in mice. Pharmacological inhibition of VEGF signaling suppressed neuropathic pain behaviors. Therefore, VEGFA‐related components may underlie peripheral neuroinflammation leading to neuropathic pain.