Recombinant Treponema pallidum protein Tp47 induces angiogenesis by modulating the matrix metalloproteinase/tissue inhibitor of metalloproteinase balance in endothelial cells

• Published in: Journal of the European Academy of Dermatology and Venereology 2019-10, Vol.33 (10), p.1958-1970
• Main Authors: Gao, Z.‐X., Luo, X., Liu, L.‐L., Lin, L.‐R., Tong, M.‐L., Yang, T.‐C.
• Format: Article
• Language: English
• Subjects: Angiogenesis Inducing Agents - pharmacology; Animals; beta-Lactamases - pharmacology; Cell Movement - drug effects; Cell Proliferation - drug effects; Gene Expression - drug effects; Human Umbilical Vein Endothelial Cells; Humans; Matrix Metalloproteinase 1 - genetics; Matrix Metalloproteinase 1 - metabolism; Matrix Metalloproteinase 10 - genetics; Matrix Metalloproteinase 10 - metabolism; Neovascularization, Pathologic - genetics; Neovascularization, Pathologic - physiopathology; Neovascularization, Physiologic - drug effects; Neovascularization, Physiologic - genetics; Proto-Oncogene Proteins c-akt - metabolism; Recombinant Proteins - pharmacology; RNA, Messenger - metabolism; RNA, Small Interfering - pharmacology; Signal Transduction - drug effects; Tissue Inhibitor of Metalloproteinase-1 - genetics; Tissue Inhibitor of Metalloproteinase-1 - metabolism; Tissue Inhibitor of Metalloproteinase-2 - genetics; Tissue Inhibitor of Metalloproteinase-2 - metabolism; TOR Serine-Threonine Kinases - metabolism; Zebrafish - embryology
• ISSN: 0926-9959; 1468-3083
• DOI: 10.1111/jdv.15725

Background Although angiogenesis is an obvious pathological manifestation in the pathogenesis of syphilis, little is known about the underlying mechanisms of angiogenesis induced by reactions to Treponema pallidum antigens. Objective In this study, we sought to determine the role of recombinant T. pallidum Tp47 in promoting angiogenesis in endothelial cells and the related mechanism. Methods Evaluation of the pro‐angiogenic activity of recombinant T. pallidum Tp47 in human umbilical vein endothelial cells (HUVECs) was assessed, and the balance of matrix metalloproteinase (MMP)/tissue inhibitor of metalloproteinase (TIMP) and the mechanisms underlying the involvement of Akt/mTOR/S6 pathways in this process were explored. Results Under stimulation by Tp47, HUVECs exhibited obvious proliferation, migration and tube formation. In addition, the apparent promotion of angiogenesis by Tp47 was observed using a zebrafish embryo model. During angiogenesis, the levels of MMP‐1 and MMP‐10 were significantly elevated, whereas those of TIMP‐1 and TIMP‐2 did not change. In addition, after transfection with siRNAMMP‐1 and siRNAMMP‐10, migration and tube formation were significantly inhibited. Akt/mTOR/S6 signalling was found to be involved in upregulating MMP‐1 and MMP‐10 expression, and the sequential blockade of steps in the pathways effectively prevented Tp47‐induced angiogenesis. Conclusion The results reveal the underlying mechanism of angiogenesis promoted by Tp47, namely, upregulating MMP‐1 and MMP‐10 expression to disrupt the MMP/TIMP balance through the Akt/mTOR/S6 pathway. These findings contribute to our understanding of the pathophysiology of syphilis.