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Circulating Exosomes Isolated from Septic Mice Induce Cardiovascular Hyperpermeability Through Promoting Podosome
Xingjiang Mu1, Xiaohong Wang1, Wei Huang2
1Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, Cincinnati, OH.
Shock (Augusta, Ga.)
|June 27, 2017
Summary
Septic shock causes vascular leakage and cardiac dysfunction. Septic exosomes deliver reactive oxygen species (ROS) to endothelial cells, promoting podosome formation and barrier damage, leading to organ failure.
Area of Science:
- Cell Biology
- Cardiovascular Research
- Pathophysiology
Background:
- Septic shock causes vascular permeability and cardiac dysfunction, contributing to mortality.
- Podosomes are actin structures involved in matrix degradation and angiogenesis.
- The role of podosomes in septic shock-induced endothelial dysfunction was previously unknown.
Purpose of the Study:
- To investigate the role of podosomes in septic shock-induced endothelial barrier dysfunction.
- To determine the mechanism by which septic exosomes affect endothelial cells.
- To explore the link between podosomes, vascular leakage, and cardiac dysfunction in sepsis.
Main Methods:
- Induction of endothelial hyperpermeability using phorbol 12-myristate 13-acetate and thrombin.
- Analysis of podosome cluster formation in cardiac endothelial cells.
- Collection and characterization of exosomes from septic mice.
- In vitro and in vivo assessment of vascular permeability and cardiac function.
- Measurement of reactive oxygen species (ROS) in exosomes and endothelial cells.
- Assessment of zonula occludens-1 (ZO-1) localization.
Main Results:
- Endothelial hyperpermeability correlated with increased podosome cluster formation.
- Septic exosomes stimulated podosome formation, increased vascular permeability, and caused cardiac dysfunction.
- Septic exosomes carried higher levels of ROS, which induced podosome formation and vascular leakage.
- ROS depletion from septic exosomes reduced their detrimental effects.
- Podosome cluster formation led to zonula occludens-1 (ZO-1) fragmentation and endothelial barrier disruption.
Conclusions:
- Septic exosomes enriched with ROS contribute to endothelial barrier dysfunction and cardiac dysfunction in septic shock.
- Exosome-derived ROS promote podosome cluster formation, leading to ZO-1 disruption and vascular leakage.
- Targeting exosome-mediated ROS transport or podosome formation may offer therapeutic strategies for septic shock.
