VEGF-A/VEGFR-1: a painful astrocyte-mediated signaling blocked by the anti-VEGFR-1 mAb D16F7

Micheli, L.; Parisio, C.; Lucarini, E.; Vona, A.; Toti, A.; Pacini, A.; Mello, T.; Boccella, S.; Ricciardi, F.; Maione, S.; Graziani, G.; Lacal, P. M.; Failli, P.; Ghelardini, C.; Di Cesare Mannelli, L.

doi:10.1101/2021.01.19.427244

bioRxiv · 10.1101/2021.01.19.427244

VEGF-A/VEGFR-1: a painful astrocyte-mediated signaling blocked by the anti-VEGFR-1 mAb D16F7

Micheli, L.·Parisio, C.·Lucarini, E.·Vona, A.·Toti, A.·Pacini, A.·Mello, T.·Boccella, S.·Ricciardi, F.·Maione, S.·Graziani, G.·Lacal, P. M.·Failli, P.·Ghelardini, C.·Di Cesare Mannelli, L.

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Abstract

Chemotherapy-induced neuropathic pain is a clinically relevant adverse effect of several anticancer drugs leading to dose reduction or therapy discontinuation. The lack of knowledge about the mechanisms of neuropathy development and pain chronicization makes chemotherapy-induced neuropathic pain treatment an unmet medical need. In this context, the vascular endothelial growth factor A (VEGF-A) has emerged as a neurotoxicity biomarker in a model of chemotherapy-induced neuropathy, and its decrease has been related to pain relief. Aim of this study was to clarify the VEGF-A-dependent pain signaling in the CNS for individuating new targeted therapeutic approaches. In mice, the intrathecal infusion of VEGF-A induced a dose-dependent noxious hypersensitivity mediated by the VEGF receptor 1 (VEGFR-1) as demonstrated by pharmacological and genetic tools. In electrophysiological study, VEGF-A stimulated the spinal nociceptive neurons activity through VEGFR-1. In the dorsal horn of the spinal cord, VEGF-A increased in astrocytes of animals affected by neuropathy suggesting this cell population as a source of the potent pain mediator. Accordingly, the selective knockdown of astrocytic VEGF-A, by shRNAmir, blocked the development of oxaliplatin-induced neuropathic pain. Besides, the anti-VEGFR-1 mAb D16F7 (previously described as anticancer) effectively relieved neuropathic pain induced by chemotherapeutic agents. In conclusion, astrocyte-released VEGF-A is a new player in the complex neuron-glia network that oversees physiological and pathological pain and D16F7 mAb rises as a potent pain killer strategy.

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Micheli, L., Parisio, C., Lucarini, E., Vona, A., Toti, A., Pacini, A., Mello, T., Boccella, S., Ricciardi, F., Maione, S., Graziani, G., Lacal, P. M., Failli, P., Ghelardini, C., Di Cesare Mannelli, L.. 2021-01-19. VEGF-A/VEGFR-1: a painful astrocyte-mediated signaling blocked by the anti-VEGFR-1 mAb D16F7. https://doi.org/10.1101/2021.01.19.427244

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