Impact of bacterial pneumonia on endothelial regeneration and immune cell differentiation in a murine vascular injury model

Johann Rößler (Berlin)1, P. Ramezani Rad (Berlin)1, L. Peters (Berlin)2, V. Nageswaran (Berlin)1, L. Reinshagen (Berlin)1, N. Kränkel (Berlin)1, S. Simmons (Berlin)3, C. Wittig (Berlin)2, R. Sculzek (Berlin)2, U. Behrendt (Berlin)2, M. Brack (Berlin)2, G. Nouailles-Kursar (Berlin)2, M. Witzenrath (Berlin)4, U. Landmesser (Berlin)1, W. Kübler (Berlin)2, A. Haghikia (Berlin)1

1Charité - Universitätsmedizin Berlin CC 11: Med. Klinik für Kardiologie Berlin, Deutschland; 2Charité - Universitätsmedizin Berlin Institut für Physiologie Berlin, Deutschland; 3Institut für Physiologie, Charité - Universitätsmedizin Berlin Labor für Lungenkreislaufforschung, Nachwuchsgruppe Immunodynamik Berlin, Deutschland; 4Charité - Universitätsmedizin Berlin CC12: Med. Klinik m. S. Infektiologie und Pneumologie Berlin, Deutschland


Background and aims

Respiratory infections are associated with an increased risk of major adverse cardiovascular events, particularly in patients with pre-existing cardiovascular conditions. However, the underlying mechanisms linking pneumonia with cardiovascular risk are still only poorly understood. Here, we aimed to investigate the impact of bacterial pneumonia with respect to potential detrimental effects on endothelial inflammation, thrombogenicity and regeneration after injury.



Methods and results

Mice (C57BL/6) were infected with Streptococcus pneumoniae (; n=10) or vehicle (PBS; n=10) via intranasal inoculation and antibiotically treated (ampicillin) starting 24 hours post infection (p.i.). Seven days p.i. carotid artery injury (CI) was induced by bipolar electrical stimulation. Three days post CI (cumulatively 10 days p.i.) mice were sacrificed and the injured area was quantified by Evans Blue staining.   

As indicated by Evans Blue staining, bacterial pneumonia impaired repair potential of the endothelium after injury. Plasma proteome profiling (Olink, Sweden) further identified significantly heightened glucagon levels in infected mice, which was validated by ELISA. Improved vascular regeneration upon additional treatment with the GLP-1-receptor-agonist liraglutide (100µg/kg bw; 0h, 24h and 48h p.i.) indicated a potential role for glucagon on the endothelium. Therefore, we analyzed the influence of glucagon on endothelial inflammation in vitro, treating primary human aortic endothelial cells (HAECs) with glucagon (10nM and 100nM; 6h). We observed a significant increase in the expression of the adhesion-molecules ICAM-1 and E-Selectin assessed by flow cytometry as well as increased monocyte adhesion. Furthermore, analysis of mitochondrial respiration by Seahorse mito stress test in vitro displayed a significantly reduced maximal respiration and spare capacity following glucagon stimulation, indicating impaired mitochondrial function. Moreover, glucagon fostered vascular thrombogenicity as demonstrated by increased thrombocyte adhesion to endothelial cells in vitro and accelerated carotid artery thrombus formation in vivo, which was prevented by treatment with liraglutide. 




Our findings reveal a novel mechanism that associates elevated circulatory glucagon levels to endothelial inflammation with reduced regenerative capacity and increased vascular thrombogenicity, suggesting lowering of blood glucagon as a potential target to prevent pneumonia-induced cardiovascular events. 

Diese Seite teilen