A link between periodontitis and atherothrombosis has been highlighted. The aim of this study was to determine the influence of Porphyromonas gingivalis on endothelial microvesicles (EMV pg) shedding and their contribution to endothelial inflammation. Endothelial cells (EC) were infected with P. gingivalis (MOI = 100) for 24 h. EMV pg were isolated and their concentration was evaluated by prothrombinase assay. EMV pg were significantly increased in comparison with EMV ctrl shedded by unstimulated cells. While EMV ctrl from untreated EC had no effect, whereas, the proportion of apoptotic EC was increased by 30 nM EMV pg and viability was decreased down to 25%, a value elicited by P. gingivalis alone. Moreover, high concentration of EMV pg (30 nM) induced a pro-inflammatory and pro-oxidative cell response including up-regulation of TNF-α, IL-6 and IL-8 as well as an altered expression of iNOS and eNOS at both mRNA and protein level. An increase of VCAM-1 and ICAM-1 mRNA expression (4.5 folds and 3 folds respectively (p < 0.05 vs untreated) was also observed after EMV pg (30 nM) stimulation whereas P. gingivalis infection was less effective, suggesting a specific triggering by EMV pg. Kinasome analysis demonstrated the specific effect induced by EMV pg on main pro-inflammatory pathways including JNK/AKT and STAT. EMV pg are effective pro-inflammatory effectors that may have detrimental effect on vascular homeostasis and should be considered as potential autocrine and paracrine effectors involved in the link between periodontitis and atherothrombosis. Periodontitis is an infectious inflammatory disease associated with soft tissue inflammation and destruction of the tooth-supporting tissues characterized by increased periodontal pocket depth, gingival bleeding and clinical attachment loss. Such disease impairs oral health related quality of life and is considered the main cause of dental mobility and tooth loss 1. Periodontitis affects a large proportion of the worldwide population and prevalence of its severe forms is estimated to be around 11% with a peak incidence around 38 years of age 2. The development of periodontitis is associated with the establishment of a dysbiosis characterized by the predominance of anaerobic species, including Porphyromonas gingivalis (P. gingivalis), and an imbalanced host-immune response inducing periodontal tissue destruction 3. During the last decades, periodontal diseases were associated with various chronic diseases such as diabetes, rheumatoid arthritis, adverse pregnancy outcomes and cardiovascular diseases, suggesting a systemic impact 4-6 with an enhanced proportion of worsened cardiovascular outcomes 7-9. Indeed, patients with periodontitis are more prone to endothelial dysfunction, aneurysmal disease progression 10 , coronary artery narrowing, and an increased all-cause and cardio-vascular related mortality 11,12. Moreover, in a clinical trial, intensive periodontal

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Markers of early pancreatic islet graft dysfunction and its causes are lacking. We monitored 19 T1D islet-transplanted patients for up to 36 months following last islet injection. Patients were categorized as Partial (PS) or complete (S) Success, or Graft Failure (F), using the βscore as an indicator of graft function. F was the subset reference of maximum worsened graft outcome. To identify the immune, pancreatic, and liver contribution to the graft dysfunction, the cell origin and concentration of circulating micro vesicles (MVs) were assessed, including MVs from insulin-secreting ß-cells typified by PSA-NCAM, and data were compared with values of the β-score. Similar ranges of PSA-NCAM + -MVs were found in healthy volunteers and S patients, indicating minimal cell damage. In PS, a 2-fold elevation in PSA-NCAM + -MVs preceded each β-score drop along with a concomitant rise in insulin needs, suggesting ß-cell damage or altered function. Significant elevation of liver ASGPR + -MVs, endothelial CD105 + -MVs, neutrophil CD66b + -MVs, monocyte CD 14 + -MVs, Accepted Article Accepted Article This article is protected by copyright. All rights reserved. and T4 lymphocyte CD4 + -MVs occurred before each -score drop, CD8 + -MVs increased only in F, B lymphocyte CD19 + -MVs remained undetectable. In conclusion, PSA-NCAM + -MVs are non-invasive early markers of transplant dysfunction, while ASGPR + -MVs signal host tissue remodeling. Leukocyte MVs could identify the cause of graft dysfunction.

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