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Coagulation factor XI regulates endothelial cell permeability and barrier function in vitro and in vivo

内皮干细胞 细胞生物学 血管通透性 生物 人脐静脉内皮细胞 势垒函数 VE钙粘蛋白 化学 生物化学 体外 内分泌学
作者
Cristina Puy,Samantha A. Moellmer,Jiaqing Pang,Helen H. Vu,Alexander R. Melrose,Christina U. Lorentz,Erik I. Tucker,Joseph J. Shatzel,Ravi S. Keshari,Florea Lupu,David Gailani,Owen J. T. McCarty
出处
期刊:Blood [American Society of Hematology]
标识
DOI:10.1182/blood.2023022257
摘要

Loss of endothelial barrier function contributes to the pathophysiology of many inflammatory diseases. Coagulation factor XI (FXI) plays a regulatory role in inflammation. While activation of FXI increases vascular permeability in vivo, the mechanism by which FXI or its activated form FXIa disrupts endothelial barrier function is unknown. We investigated the role of FXIa in human umbilical vein endothelial cell (HUVEC) or human aortic endothelial cell (HAEC) permeability. The expression patterns of vascular endothelial (VE)-cadherin and other proteins of interest were examined by Western blot or immunofluorescence. Endothelial cell permeability was analyzed by transwell assay. We demonstrate that FXIa increases endothelial cell permeability by inducing cleavage of the VE-cadherin extracellular domain, releasing a soluble fragment. The activation of a disintegrin and metalloproteinase 10 (ADAM10) mediates the FXIa-dependent cleavage of VE-cadherin, as adding an ADAM10 inhibitor prevented the cleavage of VE-cadherin induced by FXIa. The binding of FXIa with plasminogen activator inhibitor 1 and very low-density lipoprotein receptor on HUVEC or HAEC surfaces activates vascular endothelial growth receptor factor 2 (VEGFR2). The activation of VEGFR2 triggers the MAPK signaling pathway and promotes the expression of active ADAM10 on the cell surface. In a pilot experiment using an established baboon model of sepsis, the inhibition of FXI activation significantly decreased the levels of soluble VE-cadherin to preserve barrier function. This study reveals a novel pathway by which FXIa regulates vascular permeability. The effect of FXIa on barrier function may be another way by which FXIa contributes to the development of inflammatory diseases.
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