https://doi.org/10.1007/s00392-025-02625-4
1Herzzentrum der Universität zu Köln Klinik für Kardiologie, Angiologie, Pneumologie und Internistische Intensivmedizin Köln, Deutschland; 2Herzzentrum der Universität zu Köln Klinik III für Innere Medizin Köln, Deutschland; 3Fraunhofer-Institut für Molekularbiologie und Angewandte Oekologie IME Gießen, Deutschland; 4Uniklinik Köln Poliklinik für Zahnerhaltung und Parodontologie Köln, Deutschland
Background: Periodontitis, a prevalent chronic inflammatory condition of the gums, has been implicated in the pathogenesis of atherosclerosis. Systemic inflammation driven by periodontitis stimulates hematopoietic stem cells (HSCs) within the bone marrow. Prolonged inflammatory signaling may impair HSC self-renewal, contributing to HSC exhaustion and functional decline, and could selectively promote the expansion of mutant clonal populations, thereby exacerbating atherosclerotic progression.
Objective: To characterize atherosclerotic development and hematopoietic potential during chronic periodontitis.
Methods: We performed ligature-induced periodontitis (LIP) in 8–12-week-old male and female ApoE-/- mice. We placed bilateral 6-0 silk sutures around the second maxillary molars in general anesthesia, followed by a high fat, high cholesterol (1,25%) diet for up to 12 weeks. Sham animals served as controls. Separate cohorts were investigated at baseline, day 9, week 6 and 12 after ligation. Atherosclerotic burden was quantified by Oil red O staining of en face aortic whole mounts and aortic root sections. LIP severity was measured by micro-CT of the maxilla. Differential blood counts quantified systemic inflammation. Leukocyte composition in the gum and HSC progenitor populations in the bone marrow were analyzed by spectral flow cytometry.
Results: Mean surgery duration for LIP/Sham was 13 ± 2 minutes across all operated animals (n=15). LIP led to substantial bone resorption by means of cemento-enemal-junction-to-alveolar-bone-crest distance in maxillary microCT-sections, compared to sham controls (390µm vs. 195µm; P<0.001). Peripheral blood leukocyte counts were significantly elevated in LIP-treated animals compared to sham controls, 9 days after ligation (6.2x10^3/ul vs. 3.3x10^3/ul; P=0.016). Additionally, multicolor spectral flow cytometry of gingival tissue, 6 weeks after surgery, showed chronic inflammation within gum tissue of LIP animals, indicated by increased TIMD4- CCR2+ macrophages (2597 vs. 1511; P=0.047). En face Oil Red O stainings of aortic whole mounts, demonstrated an increase in aortic plaque burden (%) in LIP mice, compared to controls at 6 weeks (9.8% vs. 6%; P=0.005). Simultaneously, we found a reduction in HSCs (7353 vs. 12523 cells/femur; P=0.012) and granulocyte/monocyte progenitors (GMPs) (80744 vs. 111534 cells/femur; P=0.031) in the bone marrow of LIP animals. No significant changes in extramedullary hematopoiesis were observed.
Conclusion: Our data provide strong evidence that periodontitis accelerates atherosclerosis in mice and induces lasting alterations in medullary hematopoiesis, pointing to hematopoietic exhaustion driven by chronic inflammation. Future studies will investigate immunometabolic changes in hematopoietic and leukocyte populations to identify potential therapeutic targets for modulating maladaptive hematopoiesis in periodontitis-driven atherosclerosis.