Open AccessExtracellular vesicles released from p18 overexpressing pulmonary endothelial cells are barrier protective – potential implications for acute respiratory distress syndrome
Author(s) -
Harrington Elizabeth O.,
Braza Julie,
Shil Aparna,
Chichger Havovi
Publication year - 2020
Publication title -
pulmonary circulation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.791
H-Index - 40
ISSN - 2045-8940
DOI - 10.1177/2045894020951759
Subject(s) - extracellular , microbiology and biotechnology , endothelium , extracellular vesicle , endothelial stem cell , endosome , lipopolysaccharide , vascular permeability , vesicular transport protein , medicine , biology , microvesicles , immunology , vesicle , intracellular , in vitro , biochemistry , pathology , microrna , membrane , gene
The novel endosome protein, p18, and the early endosome GTPase, Rab4, play a significant role in protecting the pulmonary vasculature against permeability associated with acute respiratory distress syndrome. Recently, endothelial‐derived extracellular vesicles have been identified to play a key role in the endothelial permeability associated with acute respiratory distress syndrome. Therefore, we investigated the effect of these microparticles, released from endothelial cells overexpressing p18 and Rab4, on pulmonary endothelial barrier function. Endothelial‐derived extracellular vesicles isolated from lung microvascular endothelial cells which overexpressed cDNA for wild‐type p18 protected a naïve monolayer against lipopolysaccharide‐induced permeability. In contrast, endothelial‐derived extracellular vesicles from cells overexpressing the non‐endosomal binding p18 mutant (p18 N39 ) exerted no protective effect on the endothelial monolayer. Cells overexpressing either dominant active or inactive Rab4 released endothelial‐derived extracellular vesicles which had no effect on lipopolysaccharide‐induced permeability. miRNA analysis and permeability studies of endothelial‐derived extracellular vesicle isolated from wild‐type p18‐overexpressing cells demonstrates that let‐7i‐5p, miR‐96‐5p, and miR‐137‐3p are endothelial‐derived extracellular vesicle cargo which exert protective effects on the pulmonary endothelium. Finally, we observed down‐regulation of p18 protein expression in both the lung and endothelium in an in vivo and in vitro model of acute respiratory distress syndrome. These results demonstrate that endothelial‐derived extracellular vesicle released from cells overexpressing p18, but not Rab4, contain miRNA cargo which likely promote a barrier‐protective effect on the pulmonary endothelium in settings of acute respiratory distress syndrome. Findings indicate the importance of p18 in the pulmonary vasculature and demonstrate that targeting this protein may provide a novel therapeutic strategy to reduce endothelial permeability associated with acute respiratory distress syndrome.