https://orcid.org/0000-0002-1502-8781
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Abstract
Purpose
Myocardial ischemia-reperfusion injury after myocardial infarction has always been a difficult problem in clinical practice. Endothelial cells and their secreted extracellular vesicles are closely related to inflammation, thrombosis formation, and other processes after injury. Meanwhile, low-molecular-weight gelators have shown great potential for nasal administration. This study aims to explore the therapeutic effects and significance of endothelial cell-derived extracellular vesicles combined with a hydrogel for nasal administration on myocardial ischemia-reperfusion injury.
Methods
We chose a gel system composed of a derivative of glutamine amide and benzaldehyde as the extracellular vesicle delivery vehicle. This hydrogel was combined with extracellular vesicles extracted from mouse aortic endothelial cells and administered multiple times intranasally in a mouse model of ischemia-reperfusion injury to the heart. The delivery efficiency of the extracellular vesicle-hydrogel combination was evaluated by flow cytometry and immunofluorescence. Echocardiography, TTC Evan’s Blue and Masson’s staining were used to assess mouse cardiac function, infarct area, and cardiac fibrosis level. Flow cytometry, ELISA, and immunofluorescence staining were used to investigate changes in mouse inflammatory cells, cytokines, and vascular neogenesis.
Results
The vesicles combined with the hydrogel have good absorption in the nasal cavity. The hydrogel combined with vesicles reduces the levels of pro-inflammatory Ly6C (high) monocytes/macrophages and neutrophils. It can also reduce the formation of microcirculation thrombi in the infarcted area, improve endothelial barrier function, and increase microvascular density in the injured area. As a result, the heart function of mice is improved and the infarct area is reduced.
Conclusion
We first demonstrated that the combination of extracellular vesicles and hydrogel has a better absorption efficiency in the nasal cavity, which can improve myocardial ischemia-reperfusion injury by inhibiting inflammatory reactions and protecting endothelial function. Nasal administration of vesicles combined with hydrogel is a potential therapeutic direction.
Graphical Abstract
Abbreviations
IR, Ischemia-reperfusion; ECs, Endothelial cells; EVs, Extracellular vesicles; MAECs, Mouse aortic endothelial cells; AAR, Area of risk; DW/WW, The ratio of dry lung weight to wet lung weight; HW/TL, Heart weight to tibia length.
Data Sharing Statement
The detailed experimental methods and additional figures can be found in the Supplementary Materials. The data that support the findings of this study are available from the corresponding author upon reasonable request.
Ethics Approval and Informed Consent
All animal procedures conformed to the Guide for Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH; 8th edition, 2011) and were approved by and conducted according to the regulations and guidelines of the Institutional Ethics Committee of Nanjing Drum Tower Hospital (Approval No. 2023AE01020).
Author Contributions
All authors have made significant contributions to the work reported, including conception, study design, execution, data acquisition, analysis and interpretation, as well as manuscript drafting, revision, and critical review. All authors have provided final approval of the submitted version for publication and have agreed to the journal to which the article has been submitted, with full accountability for all aspects of the work.
Disclosure
The authors report no conflicts of interest in this work.