Mechanisms of vascular damage by systemic dissemination of the oral pathogenPorphyromonas gingivalis

Several studies have shown a clear association between periodontal disease and increased risk of cardiovascular disease.Porphyromonas gingivalis(Pg), a key oral pathogen, and its cell surface-expressed gingipains, induce oedema in a zebrafish larvae infection model although the mechanism of these vascular effects is unknown. Here, we aimed to determine whetherPg-induced vascular damage is mediated by gingipains.In vitro, human endothelial cells from different vascular beds were invaded by wild-type (W83) but not gingipain-deficient (Delta K/R-ab)Pg. W83 infection resulted in increased endothelial permeability as well as decreased cell surface abundance of endothelial adhesion molecules PECAM-1 and VE-cadherin compared to infection with Delta K/R-ab. In agreement, when transgenic zebrafish larvae expressing fluorescently labelled PECAM-1 or VE-cadherin were systemically infected with W83 or Delta K/R-ab, a significant reduction in adhesion molecule fluorescence was observed specifically in endothelium proximal to W83 bacteria through a gingipain-dependent mechanism. Furthermore, this was associated with increased vascular permeabilityin vivowhen assessed by dextran leakage microangiography. These data are the first to show thatPgdirectly mediates vascular damagein vivoby degrading PECAM-1 and VE-cadherin. Our data provide a molecular mechanism by whichPgmight contribute to cardiovascular disease.

Automated summary

Studies have shown a clear association between periodontal disease and increased risk of cardiovascular disease. Pg directly mediates vascular damage by degrading PECAM-1 and VE-cadherin, providing a potential molecular mechanism for the contribution of Pg to cardiovascular disease.