2. Academic Validation
  3. G3BP1 maintains endothelial barrier integrity through dual mechanisms: direct stabilization of junction protein mRNAs and suppression of the inflammatory MYD88-ARNO-ARF6 pathway

G3BP1 maintains endothelial barrier integrity through dual mechanisms: direct stabilization of junction protein mRNAs and suppression of the inflammatory MYD88-ARNO-ARF6 pathway

  • Angiogenesis. 2025 Aug 25;28(4):46. doi: 10.1007/s10456-025-09993-5.
Weiyue Sun 1,  Haoran Wu 2,  Yuxi He 1,  Huiqiao Chen 3,  Yuanhui Meng 1,  Guofang Tang 4,  Jinshun Zhu 1,  Zhengwang Wen 1,  Hui Zhang 1,  Rongzhou Wu 1,  Guowei Wu 1,  Chunxiang Zhang 5,  Maoping Chu 6,  Bin Wen 7
Affiliations

Affiliations

  • 1 Children's Heart Center, Institute of Cardiovascular Development and Translational Medicine, Zhejiang Provincial Clinical Research Center for Pediatric Disease, the Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University, Wenzhou, 325027, Zhejiang, China.
  • 2 Department of Cardiology, Key Laboratory of Medical Electrophysiology, Ministry of Education, Basic Medicine Research Innovation Center for Cardiometabolic Diseases, Ministry of Education, The Affiliated Hospital of Southwest Medical University, Southwest Medical University, Luzhou, 646000, China.
  • 3 Department of Hematology and Cell Therapy, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China.
  • 4 Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, China.
  • 5 Department of Cardiology, Key Laboratory of Medical Electrophysiology, Ministry of Education, Basic Medicine Research Innovation Center for Cardiometabolic Diseases, Ministry of Education, The Affiliated Hospital of Southwest Medical University, Southwest Medical University, Luzhou, 646000, China. zhangchx999@163.com.
  • 6 Children's Heart Center, Institute of Cardiovascular Development and Translational Medicine, Zhejiang Provincial Clinical Research Center for Pediatric Disease, the Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University, Wenzhou, 325027, Zhejiang, China. chumaoping@wmu.edu.cn.
  • 7 Children's Heart Center, Institute of Cardiovascular Development and Translational Medicine, Zhejiang Provincial Clinical Research Center for Pediatric Disease, the Second Affiliated Hospital and Yuying Children's Hospital, Wenzhou Medical University, Wenzhou, 325027, Zhejiang, China. wenbin@wmu.edu.cn.
PMID: 40855241 DOI: 10.1007/s10456-025-09993-5
Abstract

Vascular permeability, crucial for organ function, relies on the endothelial barrier formed by intercellular junctions (AJs, TJs). However, mechanisms regulating these junctions and maintaining endothelial barrier integrity are incompletely understood. Here, we investigate the RNA-binding protein G3BP1's role in endothelial barrier integrity using G3bp1 knockout mice and G3BP1-deficient human endothelial cells. We found that G3BP1 loss compromised barrier function, leading to reduced AJ and TJ protein levels and increased vascular permeability, particularly under LPS-induced inflammatory conditions. Mechanistically, G3BP1 exerts dual post-transcriptional control: it directly binds to and stabilizes mRNAs of key AJ proteins (VE-cadherin, p120), ensuring their sustained expression. Concurrently, G3BP1 binds MyD88 mRNA and promotes its decay, thereby suppressing the pro-permeability MYD88-ARNO-ARF6 signaling cascade, particularly during inflammation. Pharmacological or genetic inhibition of this pathway, or VE-cadherin overexpression, partially rescued barrier defects in G3BP1-deficient models, with combined interventions showing enhanced restoration under inflammatory conditions. Our findings reveal that G3BP1 maintains vascular barrier integrity through dual post-transcriptional control: stabilizing key AJ mRNA and suppressing inflammatory signaling via MyD88 mRNA decay. Targeting G3BP1 may offer a therapeutic strategy for vascular permeability disorders.

Keywords

Adherens junctions (AJs); Endothelial barrier integrity; G3BP1; MYD88-ARNO-ARF6 signaling pathway; RNA-binding proteins; Vascular permeability.

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