Lymphangiogenesis and NOS Localization in Healing Process after Tooth Extraction in Akita Mouse

Abstract

Type I diabetes, an autoimmune disease, induces insulin deficiency, which then disrupts vascular endothelial cell function, affecting blood and lymphatic vessels. Nitric oxide (NO) is an immune-induced destructive mediator in type I diabetes, and inhibition of its production promotes arteriosclerosis. In this study, lymphangiogenesis and expression of NO synthase (NOS) during the healing process after tooth extraction were investigated immunohistochemically in control (C57BL) and Akita mice as a diabetes model. Between 1, 4, and 10 days after extraction, expression of NOS, vascular endothelial growth factor-C (VEGF-C), VEGF receptor-3 (VEGFR-3), and von Willebrand factor was strongest during the granulation tissue phase. This suggests that severe inflammation triggers regulation of NOS and these other angiogenic and lymphangiogenic factors. During the callus phase, a few days after extraction, induced osteoblasts were positive for VEGF-C and VEGFR-3 in both the control and Akita mice, suggesting that bone formation is active in this period. Bone formation in the Akita group exceeded that in the controls. Bone tissue formation was disrupted under hyperglycemic conditions, however, suggesting that such activity would be insufficient to produce new bone.

The effects of intro-oral parathyroid hormone on the healing of tooth extraction socket: an experimental study on hyperglycemic rats

“…24 The inflammation caused by diabetes would disrupt vascular endothelial cell function. 25 The expression of inflammatory cytokines such as TNF-α, IL-1 and IFN-γ in bone increased, 26,27 which contributed to the delayed healing of extraction sockets. Moreover, the high level of advanced glycosylation end products and collagen cross-linking may cause an overall negative effect on diabetic bone mechanics.…”

Pathogenesis and treatment of wound healing in patients with diabetes after tooth extraction

“…The histological healing process in extraction-sockets is a four-stage process involving the blood clot phase, the inflammation phase of granulation tissue formation, the proliferation phase with woven bone formation and the modeling and remodeling phase, as shown below (Figure 1) (17,18). Osteogenic tissue proliferates and bone maturity following trabecular bone formation occurs between 4 and 8 weeks after extraction (19,20).…”

“…However, the presence of VEGF would be insufficient to produce new bone under hyperglycemic conditions. The bone formation is disrupted due to crosslinking of advanced glycation end products (AGEs) unfavorably, in spite of induction of VEGF-C and VEGF receptor-3 positivity in Akita mouse osteoblasts after extraction (19). IGF-1 could foster the osteogenic differentiation of apical papillae stem cells, which is likely to be induced by c-Jun N-terminal kinase and p38 mitogenactivated protein kinase signaling pathways (32).…”