Importance of Neurogenic Inflammation in the Angiogenic Response of the Dental Pulp as a Defensive Response

Substance P (SP) and calcitonin gene‐related peptide (CGRP) are neuropeptides that are assembled in the cell bodies of the trigeminal nerve and are transported through axonal flow to the nerve endings in human dental pulp, mainly in type‐C nerve fibers and free nerve endings, where they are released to fulfill important biological functions. SP plays an important role in pulp tissue reparation because it stimulates angiogenesis using direct mechanisms by modulating the growth of endothelial cells and fibroblasts through the activation of growth factors such as VEGF and IGF‐1 and stimulates cell migration and proliferation to form mineralized tissue as a defense mechanism. It also uses indirect mechanisms such as binding to granulocytes or macrophages, which allow cells with angiogenic potential to be attracted. CGRP has a key role in pulp reparation because of its angiogenic potential, which is linked to endothelial cell stimulation via the cAMP‐PKA pathway, promoting cell proliferation. It boosts VEGF expression and stimulates focal adhesion kinase involved in the stabilization and maturation of blood vessels. It can stimulate growth factors that act on fibroblasts, such as HGF, IGF‐1, and bFGF, and it can also produce an effect on odontoblast‐like cells by increasing BMP‐2 expression and allowing cell proliferation after 24 h. This shows that it can contribute to mineralized matrix formation Angiogenesis is mediated by several growth factors, such as the VEGF. VEGF is released in the pulp tissue as a response to a harmful stimulus to counteract emerging hypoxic areas regulating oxygen and nutrients supply to cell populations by forming new blood vessels. VEGF is present in endothelial cells, mast cells, macrophages, lymphocytes, undifferentiated mesenchymal cells, fibroblasts, and odontoblast‐like cells, and it controls neurogenic inflammation and reparation processes in combination with SP due to its angiogenic potential. SP, CGRP, VEGF expression can be altered by the masticatory function, occlusal trauma, orthodontic movements, or a combination of occlusal trauma and orthodontic movements, which often takes place in patients under orthodontic treatment.