Vascular Endothelial Growth Factor: A Translational View in Oral Non-Communicable Diseases

Abstract

Vascular endothelial growth factors (VEGFs) are vital regulators of angiogenesis that are expressed in response to soluble mediators, such as cytokines and growth factors. Their physiologic functions include blood vessel formation, regulation of vascular permeability, stem cell and monocyte/macrophage recruitment and maintenance of bone homeostasis and repair. In addition, angiogenesis plays a pivotal role in chronic pathologic conditions, such as tumorigenesis, inflammatory immune diseases and bone loss. According to their prevalence, morbidity and mortality, inflammatory diseases affecting periodontal tissues and oral cancer are relevant non-communicable diseases. Whereas oral squamous cell carcinoma (OSCC) is considered one of the most common cancers worldwide, destructive inflammatory periodontal diseases, on the other hand, are amongst the most prevalent chronic inflammatory conditions affecting humans and also represent the main cause of tooth loss in adults. In the recent years, while knowledge regarding the role of VEGF signaling in common oral diseases is expanding, new potential translational applications emerge. In the present narrative review we aim to explore the role of VEGF signaling in oral cancer and destructive periodontal inflammatory diseases, with emphasis in its translational applications as potential biomarkers and therapeutic targets.

Keywords: VEGF; VEGFR; angiogenesis; apical periodontitis; oral cancer; oral squamous cell carcinoma; periimplantitis; periodontitis.

Figure 1

Role of VEGF signaling in OSCC. VEGF is constitutively expressed in oral squamous cell carcinoma. Its secretion can be the result of the activation of different signaling pathways, which includes: (1) the production of hypoxia inducible and HIF-2α by low oxygen levels, (2) the activation of Stat3 by CCL4 (which is constitutively expressed in OSCC) and (3) the activation of COX2 by different inflammatory molecules (commonly overexpressed in OSCC) which activate the NF-kB pathway. The activation of these pathways leads to the transcription of all four variants of VEGF (A–D), which through the activation of VEGF-R1, VEGF-R2 and VEGF-3 on blood and lymphatic endothelial cells, induces angio- and lymphogenesis. Created with BioRender.com.

Figure 2

Role of VEGF in inflammatory periodontal diseases. During inflammatory periodontal diseases VEGF transcription can be induced by the activation of two pathways: (1) in periodontal fibroblasts IL-1, LPS and reactive oxygen species (H₂O₂) may induce the transcription of VEGF through the activation of the HIF/VEGF pathway. (2) The formation of the complex IL-6/IL-6R/gp130 may activate JAK/STAT pathway enhancing the secretion of VEGF by gingival fibroblasts. Also, VEGF might be released through the MMP-mediated proteolytic cleavage from its cryptic forms from the extracellular matrix. These cellular pathways might result in the following effects: VEGF in endothelial cells inhibits apoptosis and VEGF-A/VEGFR-1 interaction induces angiogenesis in immune cells, VEGFs participates in leukocytes’ extravasation and in osteoclasts VEGFR-2/-3 are associated with alveolar bone resorption. Created with Biorender.com.