# Porphyromonas gingivalis-derived outer membrane vesicles promote vascular endothelial glycocalyx injury via the PPAD/CitH3/B3GAT1 pathway

## TL;DR

This study shows that bacteria from the mouth can damage blood vessel linings through a specific pathway involving a key gene and enzyme.

## Contribution

The novel contribution is identifying the PPAD/CitH3/B3GAT1 pathway as a mechanism by which P. gingivalis OMVs cause glycocalyx injury.

## Key findings

- Serum SDC1 and HS levels were higher in severe periodontitis patients.
- P. gingivalis OMVs reduced glycocalyx fluorescence and key component expression.
- B3GAT1 overexpression rescued glycocalyx injury, and PPAD citrullinated H3 to suppress B3GAT1.

## Abstract

The glycocalyx serves as the skeletal structure of the outer layer of endothelial cells and regulates the function of endothelial cells. Porphyromonas gingivalis (P. gingivalis) outer membrane vesicles (OMVs) exhibit the fundamental biological traits of bacteria, such as inducing inflammatory responses, damaging host cells, and delivering virulence factors to distal tissues like the cardiovascular system. This study aimed to investigate the role of P. gingivalis OMVs in vascular endothelial glycocalyx injury.

In this clinical study, serum levels of syndecan-1 (SDC1) and heparan sulfate (HS), biomarkers of endothelial glycocalyx injury, were measured and compared between patients with stage III-IV periodontitis and those with stage I-II or no periodontitis. Then, glycocalyx injury was detected using transmission electron microscopy, immunofluorescence and western blotting after vascular endothelial cells were stimulated and C57BL/6J mice were administered with P. gingivalis OMVs via tail vein injection. Transcriptomic high-throughput sequencing analysis and in vitro and in vivo rescue experiments were conducted to determine the key mechanism in glycocalyx injury. Experiments were conducted using OMVs, PPAD−OEOMVs, and ΔPPADOMVs to identify the special virulence factors in OMVs.

This study revealed that serum levels of SDC1 and HS were significantly higher in patients with stage III-IV periodontitis (P < 0.05). A marked reduction in both the fluorescence intensity of the glycocalyx and the expression levels of its key components was observed in the OMVs group compared with control group (P < 0.05). We identified the key differentially expressed gene B3GAT1 using high-throughput sequencing. Subsequent rescue experiments both in vitro and in vivo demonstrated that overexpression of B3GAT1 effectively restored glycocalyx integrity following injury (P < 0.05). Notably, Porphyromonas gingivalis peptidylarginine deiminase (PPAD) was found to promote endovascular glycocalyx injury by citrullinating histone H3, thereby decreasing the expression of B3GAT1 (P < 0.05).

Our experiments demonstrated that biomarkers of endothelial glycocalyx injury were significantly higher in patients with stage III-IV periodontitis and PPAD could enter the cell nucleus, playing a vital role in vascular endothelial glycocalyx injury through the CitH3/B3GAT1 pathway.

The online version contains supplementary material available at 10.1186/s12951-025-04015-4.