Mobilization of endothelial progenitors by recurrent bacteremias with a periodontal pathogen.
BACKGROUND
Periodontal 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.


METHODS
12-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.


RESULTS
In 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.


CONCLUSIONS
Recurrent 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.
Department of Periodontology, Operative and Preventive Dentistry, University of Bonn, Bonn, Germany.
Moritz
M
Kebschull
Manuela
M
Haupt
Søren
S
Jepsen
James
J
Deschner
Georg
G
Nickenig
Nikos
N
Werner
D000818:Animals; D016470:Bacteremia / Q000097:blood* / Q000235:genetics / Q000473:pathology; D016866:Bacteroidaceae Infections / Q000097:blood* / Q000235:genetics / Q000473:pathology; D001854:Bone Marrow Cells / Q000378:metabolism / Q000473:pathology; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D005260:Female; D051379:Mice; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic; D053244:Osteoprotegerin / Q000097:blood / Q000235:genetics; D010518:Periodontitis / Q000097:blood* / Q000235:genetics / Q000473:pathology; D016966:Porphyromonas gingivalis; D053245:RANK Ligand / Q000097:blood / Q000235:genetics; D013234:Stem Cells / Q000378:metabolism* / Q000473:pathology; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000378:metabolism
D053244:Osteoprotegerin; D053245:RANK Ligand; C493486:Tlr2 protein, mouse; C506031:Tnfrsf11b protein, mouse; C505689:Tnfsf11 protein, mouse; D051195:Toll-Like Receptor 2