Journal Article

DKFZ-2022-02818

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Activating NO-sGC crosstalk in the mouse vascular niche promotes vascular integrity and mitigates acute lung injury.

He, H. ; Yang, W. ; Su, N. ; Zhang, C. ; Dai, J. ; Han, F. ; Singhal, M. ; Bai, W. ; Zhu, X. ; Zhu, J. ; Liu, Z. ; Xia, W. ; Liu, X. ; Zhang, C. ; Jiang, K. ; Huang, W. ; Chen, D. ; Wang, Z. ; He, X. ; Kirchhoff, F. ; Li, Z. ; Liu, C. ; Huan, J. ; Wang, X. ; Wei, W. ; Wang, J. ; Augustin, H.DKFZ* ; Hu, J.

2023
Rockefeller Univ. Press New York, NY

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Please use a persistent id in citations: doi:10.1084/jem.20211422

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.

Keyword(s): Mice (MeSH) ; Animals (MeSH) ; Soluble Guanylyl Cyclase: genetics (MeSH) ; Soluble Guanylyl Cyclase: metabolism (MeSH) ; Pericytes (MeSH) ; Nitric Oxide: metabolism (MeSH) ; Lipopolysaccharides: pharmacology (MeSH) ; Acute Lung Injury: genetics (MeSH) ; Acute Lung Injury: metabolism (MeSH) ; Soluble Guanylyl Cyclase ; Nitric Oxide ; Lipopolysaccharides

Note: DKFZ-ZMBH Alliance

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Contributing Institute(s):

1. A190 Vaskuläre Onkologie und Metastasierung (A190)

Research Program(s):

1. 311 - Zellbiologie und Tumorbiologie (POF4-311) (POF4-311)

Appears in the scientific report 2023

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Essential Science Indicators ; IF >= 15 ; JCR ; PubMed Central ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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