High glucose levels contribute to vascular fibrosis via the activation of the endothelial‐to‐mesenchymal transition in periodontitis

• Published in: Journal of periodontal research Vol. 58; no. 2; pp. 225 - 236
• Main Authors: Li, Yuyang, Zhao, Yue, Song, Lutong, Xiong, Liping, Li, Wen, Wu, Wenlei, Miao, Leiying
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.04.2023
• Subjects: Biofilms; blood vessel; Blood vessels; Cell adhesion & migration; Cell migration; Cells, Cultured; Diabetes; Diabetes mellitus; Endothelial cells; endothelial‐to‐mesenchymal transition; Epithelium; Fibrosis; Flow cytometry; Glucose; Glucose - pharmacology; Gum disease; Homeostasis; Human Umbilical Vein Endothelial Cells; Humans; Immunohistochemistry; Inflammation; Inflammation - metabolism; lipopolysaccharide; Lipopolysaccharides; Metabolism; Periodontitis; Periodontitis - metabolism; Porphyromonas gingivalis; Reactive oxygen species; Signal Transduction; Transforming Growth Factor beta; Umbilical vein; Virulence factors; Porphyromonas gingivalis; endothelial-to-mesenchymal transition; blood vessel; glucose; lipopolysaccharide
• ISSN: 0022-3484; 1600-0765
• DOI: 10.1111/jre.13084

Objective To determine the changes of Porphyromonas gingivalis (P. gingivalis) growth and metabolism and identify whether the vascular epithelium change could be induced in diabetic periodontitis. Background Maintaining favourable vascular function is a precondition for periodontal regeneration. In diabetic periodontitis, high glucose levels could enhance the metabolism of pathogens, and a complex condition involving inflammation and high glucose levels would disrupt homeostasis of the epithelium and promote fibrosis by endothelial‐to‐mesenchymal transition (EndMT). Methods Porphyromonas gingivalis was cultured with glucose to judge its metabolic activity. Human umbilical vein endothelial cells (HUVECs) were treated with P. gingivalis‐lipopolysaccharide (LPS) (10 μg/ml) and/or high glucose concentrations (25 mM), and transforming growth factor (TGF)‐β inhibitor was used to block EndMT. Inflammation level was assessed by flow cytometry. Multiple biological functions including EndMT, angiopoiesis, and cell migration were analysed. Additionally, gene expressions and protein levels were determined with qPCR and western blot, respectively. Finally, blood vessels were cultured ex vivo, and EndMT and fibrosis markers were detected by immunohistochemistry. Results Glucose could promote P. gingivalis growth and biofilm formation as well as the expression of virulence factor genes including FimA, RgpA, RgpB, and Kgp. P. gingivalis‐LPS and glucose could increase intracellular reactive oxygen species (ROS) and promote fibrosis via EndMT in HUVECs, along with attenuating angiopoiesis and cell migration, which could be resumed by blocking EndMT with TGF‐β inhibitor. Vascular fibrosis was observed after the addition of glucose via EndMT regulation. Conclusion Glucose augmented the growth and metabolism of P. gingivalis and promoted fibrosis by the activation of EndMT, as well as the inhibition of angiopoiesis and cell migration.