Papadakou P, Bletsa A, Yassin M A, Karlsen T V, Wiig H, Berggreen E
1 Department of Biomedicine, University of Bergen, Bergen, Norway.
2 Department of Clinical Dentistry, University of Bergen, Bergen, Norway.
J Dent Res. 2017 Apr;96(4):467-476. doi: 10.1177/0022034516681762. Epub 2017 Jan 12.
Lymphatic vessels are important for maintenance of tissue fluid homeostasis and afferent antigen transport. In chronic inflammation, lymphangiogenesis takes place and is characterized by lymphatic endothelial cell proliferation and lymphatic hyperplasia. Vascular endothelial growth factor C (VEGFC) is the main known lymphangiogenic growth factor, and its expression is increased in periodontitis, a common chronic infectious disease that results in tissue destruction and alveolar bone loss. The role of lymphangiogenesis during development of periodontitis is unknown. Here, we test if transgenic overexpression of epithelial VEGFC in a murine model is followed by hyperplasia of lymphatic vessels in oral mucosa and if the lymphatic drainage capacity is altered. We also test if lymphatic hyperplasia protects against periodontal disease development. Transgenic keratin 14 (K14)-VEGFC mice had significant hyperplasia of lymphatics in oral mucosa, including gingiva, without changes in blood vessel vasculature. The basal lymph flow was normal but slightly lower than in wild-type mice when oral mucosa was challenged with lipopolysaccharide from Porphyromonas gingivalis. Under normal conditions, K14-VEGFC mice exhibited an increased number of neutrophils in gingiva, demonstrated enhanced phagocyte recruitment in the cervical lymph nodes, and had more alveolar bone when compared with their wild-type littermates. After induction of periodontitis, no strain differences were observed in the periodontal tissues with respect to granulocyte recruitment, bone resorption, angiogenesis, cytokines, and bone-related protein expressions or in draining lymph node immune cell proportions and vascularization. We conclude that overexpression of VEGFC results in hyperplastic lymphatics, which do not enhance lymphatic drainage capacity but facilitate phagocyte transport to draining lymph nodes. Hyperplasia of lymphatics does not protect against development of ligature-induced periodontitis.
淋巴管对于维持组织液稳态和传入抗原运输至关重要。在慢性炎症中，会发生淋巴管生成，其特征为淋巴管内皮细胞增殖和淋巴管增生。血管内皮生长因子C（VEGFC）是已知的主要淋巴管生成生长因子，其表达在牙周炎中增加，牙周炎是一种常见的慢性感染性疾病，会导致组织破坏和牙槽骨丧失。淋巴管生成在牙周炎发展过程中的作用尚不清楚。在此，我们测试在小鼠模型中上皮VEGFC的转基因过表达是否会导致口腔黏膜淋巴管增生，以及淋巴引流能力是否改变。我们还测试淋巴管增生是否能预防牙周疾病的发展。转基因角蛋白14（K14）-VEGFC小鼠口腔黏膜包括牙龈的淋巴管有显著增生，而血管脉管系统无变化。当用牙龈卟啉单胞菌的脂多糖刺激口腔黏膜时，基础淋巴流量正常，但略低于野生型小鼠。在正常条件下，与野生型同窝小鼠相比，K14-VEGFC小鼠牙龈中的中性粒细胞数量增加，颈部淋巴结中吞噬细胞募集增强，且牙槽骨更多。诱导牙周炎后，在牙周组织中，关于粒细胞募集、骨吸收、血管生成、细胞因子以及骨相关蛋白表达方面，或在引流淋巴结免疫细胞比例和血管化方面，未观察到品系差异。我们得出结论，VEGFC过表达导致淋巴管增生，这不会增强淋巴引流能力，但有助于吞噬细胞转运至引流淋巴结。淋巴管增生不能预防结扎诱导的牙周炎的发展。
