Cargando…
Mechanosensitive Rap1 activation promotes barrier function of lung vascular endothelium under cyclic stretch
Mechanical ventilation remains an imperative treatment for the patients with acute respiratory distress syndrome, but can also exacerbate lung injury. We have previously described a key role of RhoA GTPase in high cyclic stretch (CS)–induced endothelial cell (EC) barrier dysfunction. However, cellul...
Autores principales: | , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The American Society for Cell Biology
2019
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6589902/ https://www.ncbi.nlm.nih.gov/pubmed/30759056 http://dx.doi.org/10.1091/mbc.E18-07-0422 |
_version_ | 1783429450197630976 |
---|---|
author | Ke, Yunbo Karki, Pratap Zhang, Chenou Li, Yue Nguyen, Trang Birukov, Konstantin G. Birukova, Anna A. |
author_facet | Ke, Yunbo Karki, Pratap Zhang, Chenou Li, Yue Nguyen, Trang Birukov, Konstantin G. Birukova, Anna A. |
author_sort | Ke, Yunbo |
collection | PubMed |
description | Mechanical ventilation remains an imperative treatment for the patients with acute respiratory distress syndrome, but can also exacerbate lung injury. We have previously described a key role of RhoA GTPase in high cyclic stretch (CS)–induced endothelial cell (EC) barrier dysfunction. However, cellular mechanotransduction complexes remain to be characterized. This study tested a hypothesis that recovery of a vascular EC barrier after pathologic mechanical stress may be accelerated by cell exposure to physiologic CS levels and involves Rap1-dependent rearrangement of endothelial cell junctions. Using biochemical, molecular, and imaging approaches we found that EC pre- or postconditioning at physiologically relevant low-magnitude CS promotes resealing of cell junctions disrupted by pathologic, high-magnitude CS. Cytoskeletal remodeling induced by low CS was dependent on small GTPase Rap1. Protective effects of EC preconditioning at low CS were abolished by pharmacological or molecular inhibition of Rap1 activity. In vivo, using mice exposed to mechanical ventilation, we found that the protective effect of low tidal volume ventilation against lung injury caused by lipopolysaccharides and ventilation at high tidal volume was suppressed in Rap1 knockout mice. Taken together, our results demonstrate a prominent role of Rap1-mediated signaling mechanisms activated by low CS in acceleration of lung vascular EC barrier restoration. |
format | Online Article Text |
id | pubmed-6589902 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | The American Society for Cell Biology |
record_format | MEDLINE/PubMed |
spelling | pubmed-65899022019-07-09 Mechanosensitive Rap1 activation promotes barrier function of lung vascular endothelium under cyclic stretch Ke, Yunbo Karki, Pratap Zhang, Chenou Li, Yue Nguyen, Trang Birukov, Konstantin G. Birukova, Anna A. Mol Biol Cell Articles Mechanical ventilation remains an imperative treatment for the patients with acute respiratory distress syndrome, but can also exacerbate lung injury. We have previously described a key role of RhoA GTPase in high cyclic stretch (CS)–induced endothelial cell (EC) barrier dysfunction. However, cellular mechanotransduction complexes remain to be characterized. This study tested a hypothesis that recovery of a vascular EC barrier after pathologic mechanical stress may be accelerated by cell exposure to physiologic CS levels and involves Rap1-dependent rearrangement of endothelial cell junctions. Using biochemical, molecular, and imaging approaches we found that EC pre- or postconditioning at physiologically relevant low-magnitude CS promotes resealing of cell junctions disrupted by pathologic, high-magnitude CS. Cytoskeletal remodeling induced by low CS was dependent on small GTPase Rap1. Protective effects of EC preconditioning at low CS were abolished by pharmacological or molecular inhibition of Rap1 activity. In vivo, using mice exposed to mechanical ventilation, we found that the protective effect of low tidal volume ventilation against lung injury caused by lipopolysaccharides and ventilation at high tidal volume was suppressed in Rap1 knockout mice. Taken together, our results demonstrate a prominent role of Rap1-mediated signaling mechanisms activated by low CS in acceleration of lung vascular EC barrier restoration. The American Society for Cell Biology 2019-04-01 /pmc/articles/PMC6589902/ /pubmed/30759056 http://dx.doi.org/10.1091/mbc.E18-07-0422 Text en © 2019 Ke et al. “ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society for Cell Biology. http://creativecommons.org/licenses/by-nc-sa/3.0 This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License. |
spellingShingle | Articles Ke, Yunbo Karki, Pratap Zhang, Chenou Li, Yue Nguyen, Trang Birukov, Konstantin G. Birukova, Anna A. Mechanosensitive Rap1 activation promotes barrier function of lung vascular endothelium under cyclic stretch |
title | Mechanosensitive Rap1 activation promotes barrier function of lung vascular endothelium under cyclic stretch |
title_full | Mechanosensitive Rap1 activation promotes barrier function of lung vascular endothelium under cyclic stretch |
title_fullStr | Mechanosensitive Rap1 activation promotes barrier function of lung vascular endothelium under cyclic stretch |
title_full_unstemmed | Mechanosensitive Rap1 activation promotes barrier function of lung vascular endothelium under cyclic stretch |
title_short | Mechanosensitive Rap1 activation promotes barrier function of lung vascular endothelium under cyclic stretch |
title_sort | mechanosensitive rap1 activation promotes barrier function of lung vascular endothelium under cyclic stretch |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6589902/ https://www.ncbi.nlm.nih.gov/pubmed/30759056 http://dx.doi.org/10.1091/mbc.E18-07-0422 |
work_keys_str_mv | AT keyunbo mechanosensitiverap1activationpromotesbarrierfunctionoflungvascularendotheliumundercyclicstretch AT karkipratap mechanosensitiverap1activationpromotesbarrierfunctionoflungvascularendotheliumundercyclicstretch AT zhangchenou mechanosensitiverap1activationpromotesbarrierfunctionoflungvascularendotheliumundercyclicstretch AT liyue mechanosensitiverap1activationpromotesbarrierfunctionoflungvascularendotheliumundercyclicstretch AT nguyentrang mechanosensitiverap1activationpromotesbarrierfunctionoflungvascularendotheliumundercyclicstretch AT birukovkonstanting mechanosensitiverap1activationpromotesbarrierfunctionoflungvascularendotheliumundercyclicstretch AT birukovaannaa mechanosensitiverap1activationpromotesbarrierfunctionoflungvascularendotheliumundercyclicstretch |