Cargando…
Activating NO–sGC crosstalk in the mouse vascular niche promotes vascular integrity and mitigates acute lung injury
Disruption of endothelial cell (ECs) and pericytes interactions results in vascular leakage in acute lung injury (ALI). However, molecular signals mediating EC–pericyte crosstalk have not been systemically investigated, and whether targeting such crosstalk could be adopted to combat ALI remains elus...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Rockefeller University Press
2022
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9984546/ https://www.ncbi.nlm.nih.gov/pubmed/36350314 http://dx.doi.org/10.1084/jem.20211422 |
_version_ | 1784900767998541824 |
---|---|
author | He, Hao Yang, Wu Su, Nan Zhang, Chuankai Dai, Jianing Han, Feng Singhal, Mahak Bai, Wenjuan Zhu, Xiaolan Zhu, Jing Liu, Zhen Xia, Wencheng Liu, Xiaoting Zhang, Chonghe Jiang, Kai Huang, Wenhui Chen, Dan Wang, Zhaoyin He, Xueyang Kirchhoff, Frank Li, Zhenyu Liu, Cong Huan, Jingning Wang, Xiaohong Wei, Wu Wang, Jing Augustin, Hellmut G. Hu, Junhao |
author_facet | He, Hao Yang, Wu Su, Nan Zhang, Chuankai Dai, Jianing Han, Feng Singhal, Mahak Bai, Wenjuan Zhu, Xiaolan Zhu, Jing Liu, Zhen Xia, Wencheng Liu, Xiaoting Zhang, Chonghe Jiang, Kai Huang, Wenhui Chen, Dan Wang, Zhaoyin He, Xueyang Kirchhoff, Frank Li, Zhenyu Liu, Cong Huan, Jingning Wang, Xiaohong Wei, Wu Wang, Jing Augustin, Hellmut G. Hu, Junhao |
author_sort | He, Hao |
collection | PubMed |
description | Disruption of endothelial cell (ECs) and pericytes interactions results in vascular leakage in acute lung injury (ALI). However, molecular signals mediating EC–pericyte crosstalk have not been systemically investigated, and whether targeting such crosstalk could be adopted to combat ALI remains elusive. Using comparative genome-wide EC–pericyte crosstalk analysis of healthy and LPS-challenged lungs, we discovered that crosstalk between endothelial nitric oxide and pericyte soluble guanylate cyclase (NO–sGC) is impaired in ALI. Indeed, stimulating the NO–sGC pathway promotes vascular integrity and reduces lung edema and inflammation-induced lung injury, while pericyte-specific sGC knockout abolishes this protective effect. Mechanistically, sGC activation suppresses cytoskeleton rearrangement in pericytes through inhibiting VASP-dependent F-actin formation and MRTFA/SRF-dependent de novo synthesis of genes associated with cytoskeleton rearrangement, thereby leading to the stabilization of EC–pericyte interactions. Collectively, our data demonstrate that impaired NO–sGC crosstalk in the vascular niche results in elevated vascular permeability, and pharmacological activation of this crosstalk represents a promising translational therapy for ALI. |
format | Online Article Text |
id | pubmed-9984546 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Rockefeller University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-99845462023-05-09 Activating NO–sGC crosstalk in the mouse vascular niche promotes vascular integrity and mitigates acute lung injury He, Hao Yang, Wu Su, Nan Zhang, Chuankai Dai, Jianing Han, Feng Singhal, Mahak Bai, Wenjuan Zhu, Xiaolan Zhu, Jing Liu, Zhen Xia, Wencheng Liu, Xiaoting Zhang, Chonghe Jiang, Kai Huang, Wenhui Chen, Dan Wang, Zhaoyin He, Xueyang Kirchhoff, Frank Li, Zhenyu Liu, Cong Huan, Jingning Wang, Xiaohong Wei, Wu Wang, Jing Augustin, Hellmut G. Hu, Junhao J Exp Med Article Disruption of endothelial cell (ECs) and pericytes interactions results in vascular leakage in acute lung injury (ALI). However, molecular signals mediating EC–pericyte crosstalk have not been systemically investigated, and whether targeting such crosstalk could be adopted to combat ALI remains elusive. Using comparative genome-wide EC–pericyte crosstalk analysis of healthy and LPS-challenged lungs, we discovered that crosstalk between endothelial nitric oxide and pericyte soluble guanylate cyclase (NO–sGC) is impaired in ALI. Indeed, stimulating the NO–sGC pathway promotes vascular integrity and reduces lung edema and inflammation-induced lung injury, while pericyte-specific sGC knockout abolishes this protective effect. Mechanistically, sGC activation suppresses cytoskeleton rearrangement in pericytes through inhibiting VASP-dependent F-actin formation and MRTFA/SRF-dependent de novo synthesis of genes associated with cytoskeleton rearrangement, thereby leading to the stabilization of EC–pericyte interactions. Collectively, our data demonstrate that impaired NO–sGC crosstalk in the vascular niche results in elevated vascular permeability, and pharmacological activation of this crosstalk represents a promising translational therapy for ALI. Rockefeller University Press 2022-11-09 /pmc/articles/PMC9984546/ /pubmed/36350314 http://dx.doi.org/10.1084/jem.20211422 Text en © 2022 He et al. https://creativecommons.org/licenses/by-nc-sa/4.0/http://www.rupress.org/terms/This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/). |
spellingShingle | Article He, Hao Yang, Wu Su, Nan Zhang, Chuankai Dai, Jianing Han, Feng Singhal, Mahak Bai, Wenjuan Zhu, Xiaolan Zhu, Jing Liu, Zhen Xia, Wencheng Liu, Xiaoting Zhang, Chonghe Jiang, Kai Huang, Wenhui Chen, Dan Wang, Zhaoyin He, Xueyang Kirchhoff, Frank Li, Zhenyu Liu, Cong Huan, Jingning Wang, Xiaohong Wei, Wu Wang, Jing Augustin, Hellmut G. Hu, Junhao Activating NO–sGC crosstalk in the mouse vascular niche promotes vascular integrity and mitigates acute lung injury |
title | Activating NO–sGC crosstalk in the mouse vascular niche promotes vascular integrity and mitigates acute lung injury |
title_full | Activating NO–sGC crosstalk in the mouse vascular niche promotes vascular integrity and mitigates acute lung injury |
title_fullStr | Activating NO–sGC crosstalk in the mouse vascular niche promotes vascular integrity and mitigates acute lung injury |
title_full_unstemmed | Activating NO–sGC crosstalk in the mouse vascular niche promotes vascular integrity and mitigates acute lung injury |
title_short | Activating NO–sGC crosstalk in the mouse vascular niche promotes vascular integrity and mitigates acute lung injury |
title_sort | activating no–sgc crosstalk in the mouse vascular niche promotes vascular integrity and mitigates acute lung injury |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9984546/ https://www.ncbi.nlm.nih.gov/pubmed/36350314 http://dx.doi.org/10.1084/jem.20211422 |
work_keys_str_mv | AT hehao activatingnosgccrosstalkinthemousevascularnichepromotesvascularintegrityandmitigatesacutelunginjury AT yangwu activatingnosgccrosstalkinthemousevascularnichepromotesvascularintegrityandmitigatesacutelunginjury AT sunan activatingnosgccrosstalkinthemousevascularnichepromotesvascularintegrityandmitigatesacutelunginjury AT zhangchuankai activatingnosgccrosstalkinthemousevascularnichepromotesvascularintegrityandmitigatesacutelunginjury AT daijianing activatingnosgccrosstalkinthemousevascularnichepromotesvascularintegrityandmitigatesacutelunginjury AT hanfeng activatingnosgccrosstalkinthemousevascularnichepromotesvascularintegrityandmitigatesacutelunginjury AT singhalmahak activatingnosgccrosstalkinthemousevascularnichepromotesvascularintegrityandmitigatesacutelunginjury AT baiwenjuan activatingnosgccrosstalkinthemousevascularnichepromotesvascularintegrityandmitigatesacutelunginjury AT zhuxiaolan activatingnosgccrosstalkinthemousevascularnichepromotesvascularintegrityandmitigatesacutelunginjury AT zhujing activatingnosgccrosstalkinthemousevascularnichepromotesvascularintegrityandmitigatesacutelunginjury AT liuzhen activatingnosgccrosstalkinthemousevascularnichepromotesvascularintegrityandmitigatesacutelunginjury AT xiawencheng activatingnosgccrosstalkinthemousevascularnichepromotesvascularintegrityandmitigatesacutelunginjury AT liuxiaoting activatingnosgccrosstalkinthemousevascularnichepromotesvascularintegrityandmitigatesacutelunginjury AT zhangchonghe activatingnosgccrosstalkinthemousevascularnichepromotesvascularintegrityandmitigatesacutelunginjury AT jiangkai activatingnosgccrosstalkinthemousevascularnichepromotesvascularintegrityandmitigatesacutelunginjury AT huangwenhui activatingnosgccrosstalkinthemousevascularnichepromotesvascularintegrityandmitigatesacutelunginjury AT chendan activatingnosgccrosstalkinthemousevascularnichepromotesvascularintegrityandmitigatesacutelunginjury AT wangzhaoyin activatingnosgccrosstalkinthemousevascularnichepromotesvascularintegrityandmitigatesacutelunginjury AT hexueyang activatingnosgccrosstalkinthemousevascularnichepromotesvascularintegrityandmitigatesacutelunginjury AT kirchhofffrank activatingnosgccrosstalkinthemousevascularnichepromotesvascularintegrityandmitigatesacutelunginjury AT lizhenyu activatingnosgccrosstalkinthemousevascularnichepromotesvascularintegrityandmitigatesacutelunginjury AT liucong activatingnosgccrosstalkinthemousevascularnichepromotesvascularintegrityandmitigatesacutelunginjury AT huanjingning activatingnosgccrosstalkinthemousevascularnichepromotesvascularintegrityandmitigatesacutelunginjury AT wangxiaohong activatingnosgccrosstalkinthemousevascularnichepromotesvascularintegrityandmitigatesacutelunginjury AT weiwu activatingnosgccrosstalkinthemousevascularnichepromotesvascularintegrityandmitigatesacutelunginjury AT wangjing activatingnosgccrosstalkinthemousevascularnichepromotesvascularintegrityandmitigatesacutelunginjury AT augustinhellmutg activatingnosgccrosstalkinthemousevascularnichepromotesvascularintegrityandmitigatesacutelunginjury AT hujunhao activatingnosgccrosstalkinthemousevascularnichepromotesvascularintegrityandmitigatesacutelunginjury |