2. Academic Validation
  3. Activating NO-sGC crosstalk in the mouse vascular niche promotes vascular integrity and mitigates acute lung injury

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

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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