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Shock. 2018 Apr;49(4):429-441. doi: 10.1097/SHK.0000000000000928.

Circulating Exosomes Isolated from Septic Mice Induce Cardiovascular Hyperpermeability Through Promoting Podosome Cluster Formation.

Author information

1
Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, Cincinnati, OH.
2
Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, OH.
3
Department of Intensive Care Unit, The Third Affiliated Hospital of Harbin Medical University, Heilongjiang, China.
4
Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, OH.
5
Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
6
Critical Illness Research, Lawson Health Research Institute, Ontario, Canada.

Abstract

Septic shock increases vascular permeability, leading to multiple organ failure including cardiac dysfunction, a major contributor to septic death. Podosome, an actin-based dynamic membrane structure, plays critical roles in extracellular matrix degradation and angiogenesis. However, whether podosome contributes to endothelial barrier dysfunction during septic shock remains unknown. In this study, we found that the endothelial hyperpermeability, stimulated by phorbol 12-myristate 13-acetate and thrombin, was accompanied by increased formation of podosome clusters at the cell periphery, indicating a positive correlation between podosome clusters and endothelial leakage. Interestingly, we observed that circulating exosomes collected from septic mice were able to stimulate podosome cluster formation in cardiac endothelial cells, together with increased permeability in vitro/in vivo and cardiac dysfunction. Mechanistically, we identified that septic exosomes contained higher levels of reactive oxygen species (ROS) than normal ones, which were effectively transported to endothelial cells (ECs). Depletion of ROS in septic exosomes significantly reduced their capacity for promoting podosome cluster formation and thereby dampened vascular leakage. Finally, we elucidated that podosome cluster-induced endothelial hyperpermeability was associated with fragmentation/depletion of zonula occludens-1 (ZO-1) at the cell periphery. Our results demonstrate that septic exosomes were enriched with high amounts of ROS, which can be transported to ECs, leading to the generation of podosome clusters in target ECs and thereby, causing ZO-1 relocation, vascular leakage, and cardiac dysfunction.

PMID:
28650928
PMCID:
PMC5742088
DOI:
10.1097/SHK.0000000000000928
[Indexed for MEDLINE]
Free PMC Article

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