Abstract
BackgroundPeriodontal infections are independent risk factors for atherosclerosis. However, the exact mechanisms underlying this link are yet unclear. Here, we evaluate the in vivo effects of bacteremia with a periodontal pathogen on endothelial progenitors, bone marrow-derived cells capable of endothelial regeneration, and delineate the critical pathways for these effects.Methods12-week old C57bl6 wildtype or toll-like receptor (TLR)-2 deficient mice were repeatedly intravenously challenged with 109 live P. gingivalis 381 or vehicle. Numbers of Sca1+/flk1+ progenitors, circulating angiogenic cells, CFU-Hill, and late-outgrowth EPC were measured by FACS/culture. Endothelial function was assessed using isolated organ baths, reendothelization was measured in a carotid injury model. RANKL/osteoprotegerin levels were assessed by ELISA/qPCR.ResultsIn wildtype mice challenged with intravenous P.gingivalis, numbers of Sca1+/flk1+ progenitors, CAC, CFU-Hill, and late-outgrowth EPC were strongly increased in peripheral circulation and spleen, whereas Sca1+/flk1+ progenitor numbers in bone marrow decreased. Circulating EPCs were functional, as indicated by improved endothelial function and improved reendothelization in infected mice. The osteoprotegerin/RANKL ratio was increased after P. gingivalis challenge in the bone marrow niche of wildtype mice and late-outgrowth EPC in vitro. Conversely, in mice deficient in TLR2, no increase in progenitor mobilization or osteoprotegerin/RANKL ratio was detected.ConclusionRecurrent transient bacteremias, a feature of periodontitis, increase peripheral EPC counts and decrease EPC pools in the bone marrow, thereby possibly reducing overall endothelial regeneration capacity, conceivably explaining pro-atherogenic properties of periodontal infections. These effects are seemingly mediated by toll-like receptor (TLR)-2.
Highlights
Cardiovascular diseases are the leading cause of mortality in the western world
Spleen-derived early and late-outgrowth endothelial progenitor population counts were increased by P. gingivalis bacteremia
To assess the biological functional relevance of the observed strong increases in counts of the different endothelial progenitor populations, we determined the impact of a recurrent bacteremia and subsequent progenitor mobilization on endothelial function and reendothelization
Summary
Cardiovascular diseases are the leading cause of mortality in the western world Their underlying pathological condition is atherosclerosis [1]. There is ample evidence from epidemiological studies suggesting that periodontal infections are an independent risk factor for atherosclerosis [5,6,7]. Several potential mechanisms for a periodontalcardiovascular link have been proposed (for review, see [6,8]) These are conceptually based on the fact that the sizable ulcerated epithelium of the periodontal pockets [9] mediates persistent, recurrent bacteremia with pathogens (for review, see [10]). We evaluate the in vivo effects of bacteremia with a periodontal pathogen on endothelial progenitors, bone marrow-derived cells capable of endothelial regeneration, and delineate the critical pathways for these effects
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