Fig. 10.
Schematic illustration of the mechanisms underlying contributions of vascular endothelial growth factor A (VEGF-A)/vascular endothelial growth factor receptor 2 (VEGFR2) to spinal central sensitization in bone cancer pain. (A) After tumor inoculation, VEGF-A is primarily produced and released from presynaptic and postsynaptic neurons, and its receptor VEGFR2 is upregulated in spinal neurons and microglial cells. (B) After ligand-receptor binding, VEGF-A/VEGFR2 enhances neuronal sensitization via protein kinase C (PKC)-mediated NMDA receptor activation, and promotes microglial activation via Src family kinase (SFK)-mediated proinflammatory cytokine production. As a result, VEGF-A/VEGFR2 signaling regulates neuron-neuron and neuron–glia interactions in the development of spinal central sensitization, and contributes to bone cancer pain hypersensitivity. Solid lines indicate the pathways in this study. Dashed lines indicate possible pathways in other studies.