Endothelial PTP1B Deletion Promotes VWF Exocytosis and Venous Thromboinflammation

作者：Konstantinos Zifkos, Magdalena L. Bochenek, Rajinikanth Gogiraju, Stéphane Robert, Denise Pedrosa, Klytaimnistra Kiouptsi, Kateryna Moiko, Mathias Wagner, Felix Mahfoud, Philippe Poncelet, Thomas Münzel, Wolfram Ruf, Christoph Reinhardt, Laurence Panicot‐Dubois, Christophe Dubois, Katrin Schäfer · 发表于：Circulation Research · 年份：2024 · DOI：10.1161/circresaha.124.324214 · 被引用次数：18 · 研究领域：Protein Tyrosine Phosphatases、Neutrophil, Myeloperoxidase and Oxidative Mechanisms、Cell Adhesion Molecules Research

BACKGROUND: Endothelial activation promotes the release of procoagulant extracellular vesicles and inflammatory mediators from specialized storage granules. Endothelial membrane exocytosis is controlled by phosphorylation. We hypothesized that the absence of PTP1B (protein tyrosine phosphatase 1B) in endothelial cells promotes venous thromboinflammation by triggering endothelial membrane fusion and exocytosis. METHODS: Mice with inducible endothelial deletion of PTP1B (End.PTP1B-KO) underwent inferior vena cava ligation to induce stenosis and venous thrombosis. Primary endothelial cells from transgenic mice and human umbilical vein endothelial cells were used for mechanistic studies. RESULTS: Vascular ultrasound and histology showed significantly larger venous thrombi containing higher numbers of Ly6G (lymphocyte antigen 6 family member G)-positive neutrophils in mice with endothelial PTP1B deletion, and intravital microscopy confirmed the more pronounced neutrophil recruitment following inferior vena cava ligation. RT 2 PCR profiler array and immunocytochemistry analysis revealed increased endothelial activation and adhesion molecule expression in primary End.PTP1B-KO endothelial cells, including CD62P (P-selectin) and VWF (von Willebrand factor). Pretreatment with the NF-κB (nuclear factor kappa B) kinase inhibitor BAY11-7082, antibodies neutralizing CD162 (P-selectin glycoprotein ligand-1) or VWF, or arginylglycylaspartic acid integrin-blocking peptides abolished the neutr...