气候变化领域集成服务门户(CCPortal): Thrombomodulin is essential for maintaining quiescence in vascular endothelial cells

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DOI	10.1073/pnas.2022248118
	Thrombomodulin is essential for maintaining quiescence in vascular endothelial cells
	Giri H.; Panicker S.R.; Cai X.; Biswas I.; Weiler H.; Rezaie A.R.
发表日期	2021
ISSN	00278424
卷号	118 期号:11
英文摘要	Thrombomodulin (TM) is a thrombin receptor on endothelial cells that is involved in promoting activation of the anticoagulant protein C pathway during blood coagulation. TM also exerts protective anti-inflammatory properties through a poorly understood mechanism. In this study, we investigated the importance of TM signaling to cellular functions by deleting it from endothelial cells by CRISPR-Cas9 technology and analyzed the resultant phenotype of TM-deficient (TM-/-) cells. Deficiency of TM in endothelial cells resulted in increased basal permeability and hyperpermeability when stimulated by thrombin and TNF-α. The loss of the basal barrier permeability function was accompanied by increased tyrosine phosphorylation of VE-cadherin and reduced polymerization of F-actin filaments at cellular junctions. A significant increase in basal NF-κB signaling and expression of inflammatory cell adhesion molecules was observed in TM-/-cells that resulted in enhanced adhesion of leukocytes to TM-/-cells in flow chamber experiments. There was also a marked increase in expression, storage, and release of the von Willebrand factor (VWF) and decreased storage and release of angiopoietin-2 in TM-/-cells. In a flow chamber assay, isolated platelets adhered to TM-/-cells, forming characteristic VWF-platelet strings. Increased VWF levels and inflammatory foci were also observed in the lungs of tamoxifentreated ERcre-TMf/fmice. Reexpression of the TM construct in TM-/-cells, but not treatment with soluble TM, normalized the cellular phenotype. Based on these results, we postulate cellbound TM endows a quiescent cellular phenotype by tightly regulating expression of procoagulant, proinflammatory, and angiogenic molecules in vascular endothelial cells. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	CRISPR-Cas9; Inflammation; PAR1; Thrombomodulin; VWF
语种	英语
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/180240
作者单位	Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, United States; Blood Research Institute, Blood Center of Wisconsin, Milwaukee, WI 53226, United States; Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, United States
推荐引用方式 GB/T 7714	Giri H.,Panicker S.R.,Cai X.,et al. Thrombomodulin is essential for maintaining quiescence in vascular endothelial cells[J],2021,118(11).
APA	Giri H.,Panicker S.R.,Cai X.,Biswas I.,Weiler H.,&Rezaie A.R..(2021).Thrombomodulin is essential for maintaining quiescence in vascular endothelial cells.Proceedings of the National Academy of Sciences of the United States of America,118(11).
MLA	Giri H.,et al."Thrombomodulin is essential for maintaining quiescence in vascular endothelial cells".Proceedings of the National Academy of Sciences of the United States of America 118.11(2021).