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

J Exp Med. 2023 Feb 6;220(2):e20211422. doi: 10.1084/jem.20211422.

Hao He ^# ¹ ², Wu Yang ^# ¹ ², Nan Su ^# ¹ ², Chuankai Zhang ³, Jianing Dai ¹, Feng Han ¹, Mahak Singhal ⁴, Wenjuan Bai ⁵, Xiaolan Zhu ¹ ², Jing Zhu ¹ ², Zhen Liu ² ⁶, Wencheng Xia ¹ ², Xiaoting Liu ¹ ², Chonghe Zhang ¹ ², Kai Jiang ¹, Wenhui Huang ⁷, Dan Chen ¹, Zhaoyin Wang ¹ ², Xueyang He ¹ ², Frank Kirchhoff ⁷, Zhenyu Li ⁸, Cong Liu ¹ ², Jingning Huan ³, Xiaohong Wang ⁹, Wu Wei ² ⁶, Jing Wang ⁵, Hellmut G Augustin ¹⁰ ¹¹, Junhao Hu ¹ ²

Affiliations

1 Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China.
2 University of Chinese Academy of Sciences, Beijing, China.
3 Department of Burn and Plastic Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
4 Laboratory of AngioRhythms, European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
5 Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
6 Chinese Academy of Sciences Key Laboratory of Computational Biology, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, China.
7 Department of Molecular Physiology, Center for Integrative Physiology and Molecular Medicine, University of Saarland, Homburg, Germany.
8 Texas A&M Health Science Center, Bryan, TX.
9 Department of Pharmacology and Tianjin Key Laboratory of Inflammation Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.
10 Division of Vascular Oncology and Metastasis, German Cancer Research Center (DKFZ-ZMBH Alliance), Heidelberg, Germany.
11 Department of Vascular Biology and Tumor Angiogenesis, European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
# Contributed equally.

PMID: 36350314 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.

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