Neuronal TRPV1‐CGRP axis regulates peripheral nerve regeneration through ERK/HIF‐1 signaling pathway

Severe trauma frequently leads to nerve damage. Peripheral nerves possess a degree of regenerative ability, and actively promoting their recovery can help restore the sensory and functional capacities of tissues. The neuropeptide calcitonin gene-related peptide (CGRP) is believed to regulate the repair of injured peripheral nerves, with neuronal transient receptor potential vanilloid type 1 (TRPV1) potentially serving as a crucial upstream factor. In this study, we established a mouse model of sciatic nerve (SN) crush injury and found that intrathecal injection of capsaicin (Cap) activated the neuronal TRPV1-CGRP axis, thereby promoting SN repair. Conversely, the application of capsazepine (Cpz), which inhibits the neuronal TRPV1-CGRP axis, delayed SN repair. Local restoration of CGRP expression at the injury site enhanced the repair process. In vitro experiments, we employed the rat Schwann cell (SC) line RSC96 to establish an indirect co-culture model of neurons and SCs. We observed that the proliferation, migration, expression of myelination-associated proteins, and neurotrophic secretion functions of RSC96 cells are positively correlated with the degree of activation of neuronal TRPV1. Inhibition of neuronal TRPV1, followed by the restoration of CGRP levels, improved these functions in RSC96 cells. Furthermore, activation of the neuronal TRPV1-CGRP axis resulted in an upregulation of extracellular signal-regulated kinases 1/2 (ERK1/2) phosphorylation levels and an increase in hypoxia-inducible factor 1α (HIF-1α) accumulation in RSC96 cells, thereby promoting their proliferation and migration. In summary, this study demonstrates that neuronal TRPV1-CGRP axis can regulate biological behavior of SCs and axon regeneration by activating the ERK/HIF-1 signaling pathway following peripheral nerve injury. This finding clarifies the role of CGRP in neuroregulatory networks and provides a novel reference point for the development of drugs and biomaterials for treating nerve damage.