Journal of dental sciences · 2026
Oral pathogens reprogram endothelial barrier and angiotensin-converting enzyme2/endothelial nitric oxide synthase-nitric oxide signaling to promote blood pressure dysregulation.
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Hsieh Ming-Shou, Hsu Tung-Nien, Huang Chin-Sheng, Renn Ting-Yi, Kuo Kuang-Tai, Lin Kuo-Yao, Chang Wei Jen
Аннотация
BACKGROUND/PURPOSE: Although periodontal disease is associated with an increased risk of hypertension, the endothelial mechanisms linking oral inflammation to vascular dysfunction remain unclear. We investigated whether Porphyromonas gingivalis lipopolysaccharide (Pg-LPS) can directly disturb endothelial homeostasis and whether macrophage -endothelial crosstalk further worsens endothelial injury.
MATERIALS AND METHODS: Human umbilical vein endothelial cells (HUVECs) were exposed to Pg-LPS alone or co-cultured (transwell system) with Pg-LPS-primed human monocytic cells -derived macrophages. Endothelial dysfunction was assessed through nitric oxide (NO) production, endothelial nitric oxide synthase (eNOS) phosphorylation, inflammatory and adhesion molecule expression, as well as junctional and cytoskeletal changes. Macrophage activation was evaluated by nuclear factor kappa B (NF-κB) signaling and M1-like inflammatory polarization. Mechanistic studies were further carried out with inhibitors against toll-like receptor 4 (TLR4), rho-associated kinase (ROCK), NOS, and the angiotensin-converting enzyme 2 (ACE2) signaling axis.
RESULTS: Pg-LPS directly triggered endothelial inflammation, with increased interleukin-6 and -8, vascular cell adhesion molecule-1/intercellular adhesion moldcule-1 expression, enhanced reactive oxygen species and endothelial permeability. Pg-LPS also suppressed eNOS activation and NO production, and disturbed ACE/ACE2 balance. In co-culture, Pg-LPS-stimulated macrophages further aggravated endothelial inflammation, barrier dysfunction, and NO-related signaling impairment. TLR4 inhibition attenuated inflammatory and barrier-disruptive responses, while modulation of the ACE/ACE2-eNOS pathway altered endothelial NO signaling.
CONCLUSION: Pg-LPS disrupts endothelial barrier integrity and NO signaling both directly and indirectly through inflammatory macrophage-endothelial crosstalk, involving TLR2/4-NF- κB, Rho/ROCK signaling and ACE2/eNOS imbalance. These findings provide mechanistic insight into how periodontal inflammation may contribute to vascular dysfunction relevant to blood pressure dysregulation.
MATERIALS AND METHODS: Human umbilical vein endothelial cells (HUVECs) were exposed to Pg-LPS alone or co-cultured (transwell system) with Pg-LPS-primed human monocytic cells -derived macrophages. Endothelial dysfunction was assessed through nitric oxide (NO) production, endothelial nitric oxide synthase (eNOS) phosphorylation, inflammatory and adhesion molecule expression, as well as junctional and cytoskeletal changes. Macrophage activation was evaluated by nuclear factor kappa B (NF-κB) signaling and M1-like inflammatory polarization. Mechanistic studies were further carried out with inhibitors against toll-like receptor 4 (TLR4), rho-associated kinase (ROCK), NOS, and the angiotensin-converting enzyme 2 (ACE2) signaling axis.
RESULTS: Pg-LPS directly triggered endothelial inflammation, with increased interleukin-6 and -8, vascular cell adhesion molecule-1/intercellular adhesion moldcule-1 expression, enhanced reactive oxygen species and endothelial permeability. Pg-LPS also suppressed eNOS activation and NO production, and disturbed ACE/ACE2 balance. In co-culture, Pg-LPS-stimulated macrophages further aggravated endothelial inflammation, barrier dysfunction, and NO-related signaling impairment. TLR4 inhibition attenuated inflammatory and barrier-disruptive responses, while modulation of the ACE/ACE2-eNOS pathway altered endothelial NO signaling.
CONCLUSION: Pg-LPS disrupts endothelial barrier integrity and NO signaling both directly and indirectly through inflammatory macrophage-endothelial crosstalk, involving TLR2/4-NF- κB, Rho/ROCK signaling and ACE2/eNOS imbalance. These findings provide mechanistic insight into how periodontal inflammation may contribute to vascular dysfunction relevant to blood pressure dysregulation.