TY  - JOUR
AU  - He, Hao
AU  - Yang, Wu
AU  - Su, Nan
AU  - Zhang, Chuankai
AU  - Dai, Jianing
AU  - Han, Feng
AU  - Singhal, Mahak
AU  - Bai, Wenjuan
AU  - Zhu, Xiaolan
AU  - Zhu, Jing
AU  - Liu, Zhen
AU  - Xia, Wencheng
AU  - Liu, Xiaoting
AU  - Zhang, Chonghe
AU  - Jiang, Kai
AU  - Huang, Wenhui
AU  - Chen, Dan
AU  - Wang, Zhaoyin
AU  - He, Xueyang
AU  - Kirchhoff, Frank
AU  - Li, Zhenyu
AU  - Liu, Cong
AU  - Huan, Jingning
AU  - Wang, Xiaohong
AU  - Wei, Wu
AU  - Wang, Jing
AU  - Augustin, Hellmut
AU  - Hu, Junhao
TI  - Activating NO-sGC crosstalk in the mouse vascular niche promotes vascular integrity and mitigates acute lung injury.
JO  - Journal of experimental medicine
VL  - 220
IS  - 2
SN  - 0022-1007
CY  - New York, NY
PB  - Rockefeller Univ. Press
M1  - DKFZ-2022-02818
SP  - e20211422
PY  - 2023
N1  - DKFZ-ZMBH Alliance
AB  - 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.
KW  - Mice
KW  - Animals
KW  - Soluble Guanylyl Cyclase: genetics
KW  - Soluble Guanylyl Cyclase: metabolism
KW  - Pericytes
KW  - Nitric Oxide: metabolism
KW  - Lipopolysaccharides: pharmacology
KW  - Acute Lung Injury: genetics
KW  - Acute Lung Injury: metabolism
KW  - Soluble Guanylyl Cyclase (NLM Chemicals)
KW  - Nitric Oxide (NLM Chemicals)
KW  - Lipopolysaccharides (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:36350314
DO  - DOI:10.1084/jem.20211422
UR  - https://inrepo02.dkfz.de/record/182641
ER  -