1. Department of General Surgery, Tang Du Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, People's Republic of China;
2. Department of Stomatology, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210002, People's Republic of China;
3. State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, Fourth Military Medical University, Xi'an, Shaanxi 710032, People's Republic of China;
4. Department of Stomatology, General Hospital of Eastern Theater Command, PLA, Nanjing, Jiangsu 210002, People's Republic of China;
5. Xi'an Institute of Tissue Engineering and Regenerative Medicine, Xi'an, Shaanxi 710032, People's Republic of China;
6. Department of Clinical Laboratory, The First Affiliated Hospital of Xi'an Medical University, Xi'an, Shaanxi 710032, People's Republic of China.
*These authors contributed equally to the study.
Abnormal angiogenesis is one of the significant features in periodontitis leading to progressive inflammation, but angiogenic changes of periodontal ligaments under inflammatory condition were rarely reported. Periodontal ligament stem cells (PDLSCs) were a kind of dental stem cells associated with vascularization. Here we investigated the alteration of angiogenesis of periodontal ligament in periodontitis, and revealed an exosome-mediated pathway to support the effect of PDLSCs on angiogenic improvement. Vascular specific marker CD31 and VEGFA were found to be highly expressed in periodontal ligaments of periodontitis. The VEGFA expression was up-regulated in inflamed PDLSCs compared to control, meanwhile the tube formation of HUVECs was improved when co-cultured with inflamed PDLSCs. Exosomes secretion of PDSLCs was augmented by inflammation, and promoted angiogenesis of HUVECs, whereas blocking secretion of exosomes led to degenerated angiogenesis of HUVECs. Exosome-trasferred VEGFA was proven to be the crucial communicator between PDLSCs and HUVECs. Inflammation inhibited miR-17-5p expression of PDLSCs and relieved its target VEGFA. However, overexpression of miR-17-5p blocked the pro-angiogenic ability of inflamed PDLSCs. In conclusion, the findings indicated that vascularization of periodontal ligaments was enhanced, and inflammatory micro-environment of periodontitis facilitated pro-angiogenesis of PDLSCs through regulating exosome-mediated transfer of VEGFA, which was targeted by miR-17-5p.
Keywords: periodontitis, angiogenesis, PDLSCs, exosomes, miR-17-5p, VEGF