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.
ConclusionThe 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. At the second stage (secondary syphilis), T. pallidum causes a plethora of clinical manifestations characterized by vascular inflammation and increased angiogenesis. 5,6 In tertiary syphilis, unresolved angiogenesis is the underlying mechanism responsible for skeletal changes. 7 Overall, angiogenesis appears to play a pivotal role in syphilis pathogenesis, as with other diseases (e.g. cancer, infections and immune disorders). 8 † These authors contributed equally to this work.