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Activating NO–sGC crosstalk in the mouse vascular niche promotes vascular integrity and mitigates acute lung injury

Authors :
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
Source :
The Journal of Experimental Medicine; February 2023, Vol. 220 Issue: 2 pe20211422-e20211422, 1p
Publication Year :
2023

Abstract

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.

Details

Language :
English
ISSN :
00221007 and 15409538
Volume :
220
Issue :
2
Database :
Supplemental Index
Journal :
The Journal of Experimental Medicine
Publication Type :
Periodical
Accession number :
ejs61111959
Full Text :
https://doi.org/10.1084/jem.20211422