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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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Detalles Bibliográficos
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
Descripción
Sumario: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.