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Dietmar Vestweber - One of the best experts on this subject based on the ideXlab platform.
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Similarities and differences in the regulation of Leukocyte Extravasation and vascular permeability.
Seminars in immunopathology, 2014Co-Authors: Dietmar Vestweber, Florian Wessel, Astrid F. NottebaumAbstract:Leukocyte Extravasation is regulated and mediated by a multitude of adhesion and signaling molecules. Many of them enable the capturing and docking of Leukocytes to the vessel wall. Others allow Leukocytes to crawl on the apical surface of endothelial cells to appropriate sites of exit. While these steps are well understood and the adhesion molecules mediating these interactions are largely identified, a still growing number of adhesion receptors mediate the diapedesis process, the actual migration of Leukocytes through the endothelial cell layer, and the underlying basement membrane. In most cases, it is not known which molecular processes they actually mediate, whether they enable the migration of Leukocytes through the endothelial cell layer or whether they are involved in the destabilization of endothelial junctions. In addition, Leukocytes are able to circumvent junctions and transcytose directly through the body of endothelial cells. While this latter route indeed exists, recent work has highlighted in vivo the junctional pathway as the prevalent way of Leukocyte exit in various inflamed tissues. Recent work elucidating molecular mechanisms that regulate endothelial junctions and thereby Leukocyte Extravasation and vascular permeability will be discussed.
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Cutting Edge: Endothelial-Specific Gene Ablation of CD99L2 Impairs Leukocyte Extravasation In Vivo
Journal of immunology (Baltimore Md. : 1950), 2013Co-Authors: Ruth Seelige, Maike Frye, Christiane Natsch, Sigrid März, Ding Jing, Stefan Butz, Dietmar VestweberAbstract:CD99-like 2 (CD99L2) is a membrane protein with moderate sequence homology to CD99, which initiates cell aggregation of transfected cells and that is strongly expressed on endothelial cells, neutrophils, and lymphocytes. We showed recently that Abs against CD99L2 inhibit neutrophil, but not T lymphocyte, recruitment into inflamed tissues. In this study, we have generated conditional gene–deficient mice for CD99L2 and show by analyzing them in various inflammation models several results. First, gene ablation of CD99L2 impairs neutrophil recruitment into inflamed cremaster and peritoneum. Second, despite the strong expression of CD99L2 on peripheral neutrophils, only gene ablation on endothelial cells but not on myeloid cells affects neutrophil Extravasation. Third, in contrast to our previous Ab-based results, recruitment of activated T cells into inflamed skin was impaired in mice lacking CD99L2 on endothelial cells. We conclude that CD99L2 is an essential endothelial Ag for Leukocyte Extravasation, which does not require homophilic interactions with CD99L2 on Leukocytes.
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Locking endothelial junctions blocks Leukocyte Extravasation, but not in all tissues
Tissue barriers, 2013Co-Authors: Verena Küppers, Dietmar Vestweber, Dörte SchulteAbstract:The passage of Leukocytes across the blood vessel wall is a fundamental event in the inflammatory response. During the last decades, there has been significant progress in understanding the molecular mechanisms involved in Leukocyte transmigration. However, it is still a matter of debate whether Leukocytes migrate paracellularly or transcellularly through an endothelial cell layer. We could recently show that a VE-cadherin-α-catenin fusion protein locks endothelial junctions in the skin and strongly reduces Leukocyte diapedesis in lung, skin and cremaster, establishing the paracellular route as the major transmigration pathway in these tissues. However, the homing of naive lymphocytes into lymph nodes and Extravasation of neutrophils in the inflamed peritoneum were not affected by VE-cadherin-α-catenin. This unexpected heterogeneity of the diapedesis process in different tissues as well as the complexity and dynamics of the cadherin-catenin complex in regulating endothelial junctions will be discussed.
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Relevance of endothelial junctions in Leukocyte Extravasation and vascular permeability
Annals of the New York Academy of Sciences, 2012Co-Authors: Dietmar VestweberAbstract:Inflammation and immune surveillance rely on the ability of Leukocytes to leave the blood stream and enter tissue. Cytokines and chemokines regulate expression and the activation state of adhesion molecules that enable Leukocytes to adhere and arrest at sites of Leukocyte exit. Capturing and arrest is followed by the transmigration of Leukocytes through the vessel wall-a process called diapedesis. The review will focus on recently published novel approaches to determine the route that Leukocytes take in vivo when they migrate through the endothelial layer of blood vessels. This work has revealed the dominant importance of the junctional pathway between endothelial cells in vivo. In addition, recent progress has improved our understanding of the molecular mechanisms that regulate junctional stability, the opening of endothelial junctions during Leukocyte Extravasation, and the induction of vascular permeability.
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Novel insights into Leukocyte Extravasation.
Current Opinion in Hematology, 2012Co-Authors: Dietmar VestweberAbstract:PURPOSE OF REVIEW Leukocyte Extravasation is a multistep process that is regulated at various levels. This review will highlight recent findings that define new regulatory mechanisms and novel activities in the process of Leukocyte docking to the endothelium and diapedesis of Leukocytes through the endothelial barrier of the vessel wall. RECENT FINDINGS Within the past 2-3 years, novel regulatory mechanisms have been identified that control or balance Leukocyte Extravasation at different steps of the Extravasation process. First evidence was established for differences in the roles of intracellular factors that bind to integrins and support their activation. A cytokine was found that counteracts the activation of Leukocyte integrins. Not only Leukocyte integrins but also their ligands on endothelial cells were shown to arrange in clusters while supporting Leukocyte-endothelial interactions. Recent progress was made in determining in vivo the route of Leukocyte diapedesis through the endothelium of the blood vessel wall. Finally, novel mechanisms were found that control the opening of the endothelial barrier during diapedesis and others that determine directionality of diapedesis. SUMMARY Recent progress in our understanding of Leukocyte Extravasation has unraveled novel steps and mechanisms that control this process in vivo. These findings provide new insights into the mechanisms that balance the entry of Leukocytes into tissue.
Alexander Zarbock - One of the best experts on this subject based on the ideXlab platform.
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Leukocyte Extravasation and vascular permeability are each controlled in vivo by different tyrosine residues of VE-cadherin
Nature immunology, 2014Co-Authors: Florian Wessel, Mark Winderlich, Maren Holm, Maike Frye, Ronmy Rivera-galdos, Matthias Vockel, Ruth Linnepe, Ute Ipe, Anika Stadtmann, Alexander ZarbockAbstract:Tyrosine phosphorylation of the adhesion molecule VE-cadherin is assumed to affect endothelial junction integrity. However, it remains unclear whether tyrosine residues of VE-cadherin are required for the induction of vascular permeability and the regulation of Leukocyte Extravasation in vivo. We found here that knock-in mice expressing a Y685F mutant of VE-cadherin had impaired induction of vascular permeability, but those expressing a Y731F mutant did not. In contrast, mice expressing the Y731F VE-cadherin mutant showed decreased neutrophil-Extravasation in cremaster tissue, but those expressing the Y685F mutant did not. Whereas inflammatory mediators induced the phosphorylation of Tyr685 in vivo, Tyr731 showed high baseline phosphorylation. Leukocytes triggered dephosphorylation of Tyr731 via the tyrosine phosphatase SHP-2, which allowed the adaptin AP-2 to bind and initiate endocytosis of VE-cadherin. Thus, Tyr685 and Tyr731 of VE-cadherin distinctly and selectively regulate the induction of vascular permeability or Leukocyte Extravasation.
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Dissociation of VE-PTP from VE-cadherin is required for Leukocyte Extravasation and for VEGF-induced vascular permeability in vivo
The Journal of experimental medicine, 2011Co-Authors: Andre Broermann, Alexander Zarbock, Mark Winderlich, Maike Frye, Ruth Linnepe, Helena Block, Jan Rossaint, Giuseppe Cagna, Dörte Schulte, Astrid F. NottebaumAbstract:We have recently shown that vascular endothelial protein tyrosine phosphatase (VE-PTP), an endothelial membrane protein, associates with VE-cadherin and is required for optimal VE-cadherin function and endothelial cell contact integrity. The dissociation of VE-PTP from VE-cadherin is triggered by vascular endothelial growth factor (VEGF) and by the binding of Leukocytes to endothelial cells in vitro, suggesting that this dissociation is a prerequisite for the destabilization of endothelial cell contacts. Here, we show that VE-cadherin/VE-PTP dissociation also occurs in vivo in response to LPS stimulation of the lung or systemic VEGF stimulation. To show that this dissociation is indeed necessary in vivo for Leukocyte Extravasation and VEGF-induced vascular permeability, we generated knock-in mice expressing the fusion proteins VE-cadherin-FK 506 binding protein and VE-PTP-FRB* under the control of the endogenous VE-cadherin promoter, thus replacing endogenous VE-cadherin. The additional domains in both fusion proteins allow the heterodimeric complex to be stabilized by a chemical compound (rapalog). We found that intravenous application of the rapalog strongly inhibited VEGF-induced (skin) and LPS-induced (lung) vascular permeability and inhibited neutrophil Extravasation in the IL-1β inflamed cremaster and the LPS-inflamed lung. We conclude that the dissociation of VE-PTP from VE-cadherin is indeed required in vivo for the opening of endothelial cell contacts during induction of vascular permeability and Leukocyte Extravasation.
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stabilizing the ve cadherin catenin complex blocks Leukocyte Extravasation and vascular permeability
The EMBO Journal, 2011Co-Authors: Dörte Schulte, Andre Broermann, Alexander Zarbock, Alexander G. Khandoga, Verena Küppers, Nina Dartsch, Olena Kamenyeva, Friedemann Kiefer, Steffen MassbergAbstract:To determine whether Leukocytes need to open endothelial cell contacts during Extravasation, we decided to generate mice with strongly stabilized endothelial junctions. To this end, we replaced VE-cadherin genetically by a VE-cadherin–α-catenin fusion construct. Such mice were completely resistant to the induction of vascular leaks by VEGF or histamine. Neutrophil or lymphocyte recruitment into inflamed cremaster, lung and skin were strongly inhibited in these mice, documenting the importance of the junctional route in vivo. Surprisingly, lymphocyte homing into lymph nodes was not inhibited. VE-cadherin–α-catenin associated more intensely with the actin cytoskeleton as demonstrated by its membrane mobility and detergent extractability. Our results establish the junctional route as the main pathway for extravasating Leukocytes in several, although not in all tissues. Furthermore, in these tissues, plasticity of the VE-cadherin–catenin complex is central for the Leukocyte diapedesis mechanism.
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Stabilizing the VE-cadherin–catenin complex blocks Leukocyte Extravasation and vascular permeability
The EMBO journal, 2011Co-Authors: Dörte Schulte, Andre Broermann, Alexander Zarbock, Alexander G. Khandoga, Verena Küppers, Nina Dartsch, Olena Kamenyeva, Friedemann Kiefer, Steffen MassbergAbstract:To determine whether Leukocytes need to open endothelial cell contacts during Extravasation, we decided to generate mice with strongly stabilized endothelial junctions. To this end, we replaced VE-cadherin genetically by a VE-cadherin–α-catenin fusion construct. Such mice were completely resistant to the induction of vascular leaks by VEGF or histamine. Neutrophil or lymphocyte recruitment into inflamed cremaster, lung and skin were strongly inhibited in these mice, documenting the importance of the junctional route in vivo. Surprisingly, lymphocyte homing into lymph nodes was not inhibited. VE-cadherin–α-catenin associated more intensely with the actin cytoskeleton as demonstrated by its membrane mobility and detergent extractability. Our results establish the junctional route as the main pathway for extravasating Leukocytes in several, although not in all tissues. Furthermore, in these tissues, plasticity of the VE-cadherin–catenin complex is central for the Leukocyte diapedesis mechanism.
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von willebrand factor promotes Leukocyte Extravasation
Blood, 2010Co-Authors: Bjorn Petri, Tobias Goerge, Andre Broermann, Alexander Georg Khandoga, Stefan W. Schneider, Alexander Zarbock, Fritz Krombach, Hang Li, Claire JonesAbstract:von Willebrand factor (VWF) is an important player in hemostasis but has also been suggested to promote inflammatory processes. Gene ablation of VWF causes a simultaneous defect in P-selectin expression making it difficult to identify VWF-specific functions. Therefore, we analyzed whether blocking antibodies against VWF would be able to interfere with neutrophil Extravasation. We found that these antibodies inhibited neutrophil recruitment into thioglycollate-inflamed peritoneum and KC-stimulated cremaster by approximately 50%. Whereas platelet-VWF was not involved, the contribution of VWF to granulocyte recruitment was strictly dependent on the presence of platelets and the accessibility of their VWF-receptor glycoprotein Ib. Surprisingly, platelet P-selectin was largely dispensable for Leukocyte Extravasation, in agreement with our observation that anti-VWF antibodies did not affect Leukocyte rolling and adhesion. Searching for possible effects downstream of Leukocyte capture, we found that anti-VWF antibodies significantly inhibited thioglycollate-induced vascular permeability. The increase of permeability was independent of circulating granulocytes, showing that it was not a side effect of neutrophil diapedesis. Collectively, our results demonstrate that VWF-associated platelets strongly support neutrophil Extravasation at a step downstream of Leukocyte docking to the vessel wall. This step could be related to Leukocyte diapedesis facilitated by destabilization of the endothelial barrier.
Jaap D Van Buul - One of the best experts on this subject based on the ideXlab platform.
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double hit induced Leukocyte Extravasation driven by endothelial adherens junction destabilization
Journal of Immunology, 2020Co-Authors: Sofia Morsing, Ruben Bierings, Maaike Schillemans, Claudia Almardini, Annemarieke Van Stalborch, Alexander P J Vlaar, Jaap D Van BuulAbstract:During inflammation, endothelial cells are bombarded with cytokines and other stimuli from surrounding cells. Leukocyte Extravasation and vascular leakage are both prominent but believed to be uncoupled as they occur in separate spatiotemporal patterns. In this study, we investigated a "double-hit" approach on primary human endothelial cells primed with LPS followed by histamine. Using neutrophil transendothelial migration (TEM) under physiological flow assays, we found that an LPS-primed endothelium synergistically enhanced neutrophil TEM when additionally treated with histamine, whereas the effects on neutrophil TEM of the individual stimuli were moderate to undetectable. Interestingly, the double-hit-induced TEM increase was not due to decreased endothelial barrier, increased adhesion molecule expression, or Weibel-Palade body release. Instead, we found that it was directly correlated with junctional remodeling. Compounds that increased junctional "linearity" (i.e., stability) counteracted the double-hit effect on neutrophil TEM. We conclude that a compound, in this case histamine (which has a short primary effect on vascular permeability), can have severe secondary effects on neutrophil TEM in combination with an inflammatory stimulus. This effect is due to synergic modifications of the endothelial cytoskeleton and junctional remodeling. Therefore, we hypothesize that junctional linearity is a better and more predictive readout than endothelial resistance for compounds aiming to attenuate inflammation.
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Inflammation-sensitive myosin-x functionally supports Leukocyte Extravasation by Cdc42-mediated ICAM-1-rich endothelial filopodia formation
Journal of immunology (Baltimore Md. : 1950), 2018Co-Authors: Jeffrey Kroon, Jos Van Rijssel, Antje Schaefer, Mark Hoogenboezem, Floris P. J. Van Alphen, Peter L. Hordijk, Erik S.g. Stroes, Staffan Strömblad, Jacco Van Rheenen, Jaap D Van BuulAbstract:Leukocyte transendothelial migration is key to inflammation. Leukocytes first start rolling over the inflamed endothelium, followed by firmly adhering to it. Under inflammatory conditions, endothelial cells express small finger-like protrusions that stick out into the lumen. The function and regulation of these structures are unclear. We present evidence that these ICAM-1- and F-actin-rich endothelial finger-like protrusions are filopodia and function as adhesive structures for Leukocytes to transit from rolling to crawling but are dispensable for diapedesis. Mechanistically, these structures require the motor function of myosin-X, activity of the small GTPase Cdc42, and p21-activated kinase 4. Moreover, myosin-X expression is under control of TNF-α-mediated c-Jun N-terminal kinase activity and is upregulated in human atherosclerotic regions. To our knowledge, this is the first study to identify that regulation of endothelial filopodia is crucial for Leukocyte Extravasation, in particular for the initiation of Leukocyte adhesion under flow conditions.
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Crossing the Vascular Wall: Common and Unique Mechanisms Exploited by Different Leukocyte Subsets during Extravasation
Mediators of inflammation, 2015Co-Authors: Michael Schnoor, Pilar Alcaide, Mathieu-benoit Voisin, Jaap D Van BuulAbstract:Leukocyte Extravasation is one of the essential and first steps during the initiation of inflammation. Therefore, a better understanding of the key molecules that regulate this process may help to develop novel therapeutics for treatment of inflammation-based diseases such as atherosclerosis or rheumatoid arthritis. The endothelial adhesion molecules ICAM-1 and VCAM-1 are known as the central mediators of Leukocyte adhesion to and transmigration across the endothelium. Engagement of these molecules by their Leukocyte integrin receptors initiates the activation of several signaling pathways within both Leukocytes and endothelium. Several of such events have been described to occur during transendothelial migration of all Leukocyte subsets, whereas other mechanisms are known only for a single Leukocyte subset. Here, we summarize current knowledge on regulatory mechanisms of Leukocyte Extravasation from a Leukocyte and endothelial point of view, respectively. Specifically, we will focus on highlighting common and unique mechanisms that specific Leukocyte subsets exploit to succeed in crossing endothelial monolayers.
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Rho-GTPase signaling in Leukocyte Extravasation: An endothelial point of view
Cell adhesion & migration, 2014Co-Authors: Niels Heemskerk, Jos Van Rijssel, Jaap D Van BuulAbstract:Leukocyte transendothelial migration (TEM) is one of the crucial steps during inflammation. A better understanding of the key molecules that regulate Leukocyte Extravasation aids to the development of novel therapeutics for treatment of inflammation-based diseases, such as atherosclerosis and rheumatoid arthritis. The adhesion molecules ICAM-1 and VCAM-1 are known as central mediators of TEM. Clustering of these molecules by their leukocytic integrins initiates the activation of several signaling pathways within the endothelium, including a rise in intracellular Ca2+, activation of several kinase cascades, and the activation of Rho-GTPases. Activation of Rho-GTPases has been shown to control adhesion molecule clustering and the formation of apical membrane protrusions that embrace adherent Leukocytes during TEM. Here, we discuss the potential regulatory mechanisms of Leukocyte Extravasation from an endothelial point of view, with specific focus on the role of the Rho-GTPases.
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Phosphorylation at endothelial cell-cell junctions: implications for ve-cadherin function
Cell Health and Cytoskeleton, 2010Co-Authors: Ilse Timmerman, Peter L. Hordijk, Jaap D Van BuulAbstract:Endothelial cell-cell junctions are strictly regulated in order to control the barrier function of endothelium. Vascular endothelial (VE)-cadherin is one of the proteins that is crucial in this process. It has been reported that phosphorylation events control the function of VE-cadherin. This review summarizes the role of VE-cadherin phosphorylation in the regulation of endothelial cell-cell junctions and highlights how this affects vascular permeability and Leukocyte Extravasation.
Astrid F. Nottebaum - One of the best experts on this subject based on the ideXlab platform.
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Similarities and differences in the regulation of Leukocyte Extravasation and vascular permeability.
Seminars in immunopathology, 2014Co-Authors: Dietmar Vestweber, Florian Wessel, Astrid F. NottebaumAbstract:Leukocyte Extravasation is regulated and mediated by a multitude of adhesion and signaling molecules. Many of them enable the capturing and docking of Leukocytes to the vessel wall. Others allow Leukocytes to crawl on the apical surface of endothelial cells to appropriate sites of exit. While these steps are well understood and the adhesion molecules mediating these interactions are largely identified, a still growing number of adhesion receptors mediate the diapedesis process, the actual migration of Leukocytes through the endothelial cell layer, and the underlying basement membrane. In most cases, it is not known which molecular processes they actually mediate, whether they enable the migration of Leukocytes through the endothelial cell layer or whether they are involved in the destabilization of endothelial junctions. In addition, Leukocytes are able to circumvent junctions and transcytose directly through the body of endothelial cells. While this latter route indeed exists, recent work has highlighted in vivo the junctional pathway as the prevalent way of Leukocyte exit in various inflamed tissues. Recent work elucidating molecular mechanisms that regulate endothelial junctions and thereby Leukocyte Extravasation and vascular permeability will be discussed.
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Dissociation of VE-PTP from VE-cadherin is required for Leukocyte Extravasation and for VEGF-induced vascular permeability in vivo
The Journal of experimental medicine, 2011Co-Authors: Andre Broermann, Alexander Zarbock, Mark Winderlich, Maike Frye, Ruth Linnepe, Helena Block, Jan Rossaint, Giuseppe Cagna, Dörte Schulte, Astrid F. NottebaumAbstract:We have recently shown that vascular endothelial protein tyrosine phosphatase (VE-PTP), an endothelial membrane protein, associates with VE-cadherin and is required for optimal VE-cadherin function and endothelial cell contact integrity. The dissociation of VE-PTP from VE-cadherin is triggered by vascular endothelial growth factor (VEGF) and by the binding of Leukocytes to endothelial cells in vitro, suggesting that this dissociation is a prerequisite for the destabilization of endothelial cell contacts. Here, we show that VE-cadherin/VE-PTP dissociation also occurs in vivo in response to LPS stimulation of the lung or systemic VEGF stimulation. To show that this dissociation is indeed necessary in vivo for Leukocyte Extravasation and VEGF-induced vascular permeability, we generated knock-in mice expressing the fusion proteins VE-cadherin-FK 506 binding protein and VE-PTP-FRB* under the control of the endogenous VE-cadherin promoter, thus replacing endogenous VE-cadherin. The additional domains in both fusion proteins allow the heterodimeric complex to be stabilized by a chemical compound (rapalog). We found that intravenous application of the rapalog strongly inhibited VEGF-induced (skin) and LPS-induced (lung) vascular permeability and inhibited neutrophil Extravasation in the IL-1β inflamed cremaster and the LPS-inflamed lung. We conclude that the dissociation of VE-PTP from VE-cadherin is indeed required in vivo for the opening of endothelial cell contacts during induction of vascular permeability and Leukocyte Extravasation.
Dörte Schulte - One of the best experts on this subject based on the ideXlab platform.
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Locking endothelial junctions blocks Leukocyte Extravasation, but not in all tissues
Tissue barriers, 2013Co-Authors: Verena Küppers, Dietmar Vestweber, Dörte SchulteAbstract:The passage of Leukocytes across the blood vessel wall is a fundamental event in the inflammatory response. During the last decades, there has been significant progress in understanding the molecular mechanisms involved in Leukocyte transmigration. However, it is still a matter of debate whether Leukocytes migrate paracellularly or transcellularly through an endothelial cell layer. We could recently show that a VE-cadherin-α-catenin fusion protein locks endothelial junctions in the skin and strongly reduces Leukocyte diapedesis in lung, skin and cremaster, establishing the paracellular route as the major transmigration pathway in these tissues. However, the homing of naive lymphocytes into lymph nodes and Extravasation of neutrophils in the inflamed peritoneum were not affected by VE-cadherin-α-catenin. This unexpected heterogeneity of the diapedesis process in different tissues as well as the complexity and dynamics of the cadherin-catenin complex in regulating endothelial junctions will be discussed.
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Dissociation of VE-PTP from VE-cadherin is required for Leukocyte Extravasation and for VEGF-induced vascular permeability in vivo
The Journal of experimental medicine, 2011Co-Authors: Andre Broermann, Alexander Zarbock, Mark Winderlich, Maike Frye, Ruth Linnepe, Helena Block, Jan Rossaint, Giuseppe Cagna, Dörte Schulte, Astrid F. NottebaumAbstract:We have recently shown that vascular endothelial protein tyrosine phosphatase (VE-PTP), an endothelial membrane protein, associates with VE-cadherin and is required for optimal VE-cadherin function and endothelial cell contact integrity. The dissociation of VE-PTP from VE-cadherin is triggered by vascular endothelial growth factor (VEGF) and by the binding of Leukocytes to endothelial cells in vitro, suggesting that this dissociation is a prerequisite for the destabilization of endothelial cell contacts. Here, we show that VE-cadherin/VE-PTP dissociation also occurs in vivo in response to LPS stimulation of the lung or systemic VEGF stimulation. To show that this dissociation is indeed necessary in vivo for Leukocyte Extravasation and VEGF-induced vascular permeability, we generated knock-in mice expressing the fusion proteins VE-cadherin-FK 506 binding protein and VE-PTP-FRB* under the control of the endogenous VE-cadherin promoter, thus replacing endogenous VE-cadherin. The additional domains in both fusion proteins allow the heterodimeric complex to be stabilized by a chemical compound (rapalog). We found that intravenous application of the rapalog strongly inhibited VEGF-induced (skin) and LPS-induced (lung) vascular permeability and inhibited neutrophil Extravasation in the IL-1β inflamed cremaster and the LPS-inflamed lung. We conclude that the dissociation of VE-PTP from VE-cadherin is indeed required in vivo for the opening of endothelial cell contacts during induction of vascular permeability and Leukocyte Extravasation.
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stabilizing the ve cadherin catenin complex blocks Leukocyte Extravasation and vascular permeability
The EMBO Journal, 2011Co-Authors: Dörte Schulte, Andre Broermann, Alexander Zarbock, Alexander G. Khandoga, Verena Küppers, Nina Dartsch, Olena Kamenyeva, Friedemann Kiefer, Steffen MassbergAbstract:To determine whether Leukocytes need to open endothelial cell contacts during Extravasation, we decided to generate mice with strongly stabilized endothelial junctions. To this end, we replaced VE-cadherin genetically by a VE-cadherin–α-catenin fusion construct. Such mice were completely resistant to the induction of vascular leaks by VEGF or histamine. Neutrophil or lymphocyte recruitment into inflamed cremaster, lung and skin were strongly inhibited in these mice, documenting the importance of the junctional route in vivo. Surprisingly, lymphocyte homing into lymph nodes was not inhibited. VE-cadherin–α-catenin associated more intensely with the actin cytoskeleton as demonstrated by its membrane mobility and detergent extractability. Our results establish the junctional route as the main pathway for extravasating Leukocytes in several, although not in all tissues. Furthermore, in these tissues, plasticity of the VE-cadherin–catenin complex is central for the Leukocyte diapedesis mechanism.
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Stabilizing the VE-cadherin–catenin complex blocks Leukocyte Extravasation and vascular permeability
The EMBO journal, 2011Co-Authors: Dörte Schulte, Andre Broermann, Alexander Zarbock, Alexander G. Khandoga, Verena Küppers, Nina Dartsch, Olena Kamenyeva, Friedemann Kiefer, Steffen MassbergAbstract:To determine whether Leukocytes need to open endothelial cell contacts during Extravasation, we decided to generate mice with strongly stabilized endothelial junctions. To this end, we replaced VE-cadherin genetically by a VE-cadherin–α-catenin fusion construct. Such mice were completely resistant to the induction of vascular leaks by VEGF or histamine. Neutrophil or lymphocyte recruitment into inflamed cremaster, lung and skin were strongly inhibited in these mice, documenting the importance of the junctional route in vivo. Surprisingly, lymphocyte homing into lymph nodes was not inhibited. VE-cadherin–α-catenin associated more intensely with the actin cytoskeleton as demonstrated by its membrane mobility and detergent extractability. Our results establish the junctional route as the main pathway for extravasating Leukocytes in several, although not in all tissues. Furthermore, in these tissues, plasticity of the VE-cadherin–catenin complex is central for the Leukocyte diapedesis mechanism.