Abstract
Increased microvascular leakage is a cardinal feature of many critical diseases. Regular exercise is associated with improved endothelial function and reduced risk of cardiovascular disease. Irisin, secreted during exercise, contributes to many health benefits of exercise. However, the effects of irisin on endothelial function and microvascular leakage remain unknown. In this study, we found that irisin remarkably strengthened endothelial junctions and barrier function via binding to integrin αVβ5 receptor in LPS-treated endothelial cells. The beneficial effect of irisin was associated with suppression of the Src-MLCK-β-catenin pathway, activation of the AMPK-Cdc42/Rac1 pathway, and improvement of mitochondrial function. In preclinical models of microvascular leakage, exogenous irisin improved pulmonary function, decreased lung edema and injury, suppressed inflammation, and increased survival. In ARDS patients, serum irisin levels were decreased and inversely correlated with disease severity and mortality. In conclusion, irisin enhances endothelial barrier function and mitigates microvascular leakage-related diseases.
Highlights
Microvascular leakage is a pivotal pathological process in many diseases, such as asthma, sepsis, acute respiratory distress syndrome (ARDS), anaphylaxis, and diabetic retinopathy
Phalloidin and VE-cadherin were stained to assess cytoskeletal remodeling and adherens junction integrity in endothelial cells, respectively. These results showed that LPS induced massive formation of actin stress fibers and intercellular gaps due to cell contractions in human microvascular endothelial cells (HMVECs)
We found that low serum irisin was associated with worse outcomes in ARDS patients, and exogenous irisin protected against endothelial barrier dysfunction and microvascular leakage–related diseases via binding to integrin αVβ5 receptor, further inhibiting the phosphorylated Src (P-Src) (Y416)/P-MLCK
Summary
Microvascular leakage is a pivotal pathological process in many diseases, such as asthma, sepsis, acute respiratory distress syndrome (ARDS), anaphylaxis, and diabetic retinopathy. Endotoxin, inflammatory factors, and neutrophils facilitate endothelial myosin light chain (MLC) phosphorylation to combine with actin and induce the phosphorylation of β-catenin and the separation of VE-cadherin from the cytoskeleton, resulting in disruption of adhesion junctions between endothelial cells [2, 3]. Rho GTPase family members dynamically regulate intercellular junctions and cytoskeletal remodeling via the formation of cortical actin. Under disease conditions, decreased activation of Cdc and Rac and increased activation of Rho lead to cytoskeletal remodeling, resulting in endothelial cell shrinkage, intercellular broadening, and increased vascular permeability [4, 5]. Mitochondrial dysfunction, including decreased mitochondria quantity, imbalanced mitochondrial dynamics, mitochondrial fragmentation, respiratory chain inhibition, and massive ROS generation, directly damages endothelial cells and increases pulmonary endothelial permeability [6,7,8]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
