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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...

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Autores principales: 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
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
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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.
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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
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