The role of adherens junctions and VE-cadherin in the control of vascular permeability

Abstract

endothelial growth factor (VEGF), induce the tyrosine phosphorylation of VE-cadherin, which accompanies an increase in vascular permeability and leukocyte diapedesis; in addition, the internalization and cleavage of VE-cadherin can cause AJs to be dismantled. From the knowledge of how AJ organization can be modulated, it is possible to formulate several pharmacological strategies to control the barrier function of the endothelium. We discuss the possible use of inhibitors of SRC and other kinases, of agents that increase cAMP levels, and of inhibitors of lytic enzymes as pharmacological tools for decreasing endothelial permeability. Journal of Cell Science 2116 paracellular permeability is governed by the opening and closing of cell junctions, which implies that a complex rearrangement of adhesion proteins and the related cytoskeleton must occur. It is likely that the two pathways are interconnected in some way, because many permeability-increasing agents increase vesicular transport and also disrupt the integrity of endothelial cell-cell junctions (Dejana, 2004;Feng et al., 1999;Weis and Cheresh, 2005); however, whether this occurs in the same vessels and at the same time is still a matter of debate. It is possible that, in some areas of the vasculature, such as the microvasculature of the glands, the transcellular pathway is better developed, whereas in others, such as the postcapillary venules, the paracellular pathway is favored. It will be of interest, once more knowledge is available on the vesicular-transport systems in endothelial cells, to try to integrate both systems into a more comprehensive picture. This Commentary focuses on the role of cell-cell junctionsparticularly adherens junctions (AJs) -in the barrier function of the endothelium. We pay particular attention to the function, molecular organization and regulation of vascular endothelial (VE)-cadherin, the endothelium-specific transmembrane component of AJs. Finally, we show that pharmacological strategies for modulating endothelial permeability can be obtained by using our knowledge of the structure and function of AJs. Adherens junctions and vascular integrityPrevious work has described the molecular organization of the different types of endothelial cell-cell junctions, and has established a basis for understanding how these structures might crosstalk and reciprocally interact (Bazzoni and Dejana, 2004;Muller, 2003;Vestweber, 2007;Wallez and Huber, 2007). Endothelial-cell junctions present a particularly complex network of adhesion proteins that are linked to intracellular cytoskeletal and signaling partners. These proteins are organized into distinct structures called tight junctions (TJs) and AJs. In addition, several adhesion proteins [such as platelet endothelial cell adhesion molecule (PECAM1), MUC18, intercellular adhesion molecule 2 (ICAM2), CD34, endoglin and others] cluster at cell-cell contacts that are distinct from TJs and AJs. There are data to suggest that the assembly of AJs is required for the correct organization of TJs, but...

Vascular Endothelial Growth Factor C Disrupts the Endothelial Lymphatic Barrier to Promote Colorectal Cancer Invasion

“…by VEGFA which induces VE-Cad tyrosine phosphorylation and its internalization 16 . In this scenario, VEGFA facilitates cancer cell intravasation by disrupting the VE-Cad-β-catenin complex and inducing adherens junction weakness and formation of transcellular holes 34 .…”

“…One of the main restrictions of tumor cell intravasation through the lymphatic system is LV integrity 15 , which is strictly related to the organization of interendothelial adherens junction proteins. These junctions are formed by the homotypic interaction of vascular endothelial cadherin (VE-Cad) 16 . Upon cell-cell adhesion, cadherin units form a core adhesion complex on adjacent cells via their extracellular domains 16 .…”

“…These junctions are formed by the homotypic interaction of vascular endothelial cadherin (VE-Cad) 16 . Upon cell-cell adhesion, cadherin units form a core adhesion complex on adjacent cells via their extracellular domains 16 . In greater detail, the VE-Cad intracellular region forms a complex with an intracellular protein network, including α-, β-and γ-catenin and p120 17 , thus contributing to the strength of intracellular adhesion 18 .…”

Agonist of growth hormone-releasing hormone reduces pneumolysin-induced pulmonary permeability edema

“…2A) that can be significantly abolished upon a 30-min pretreatment of the cells with JI-34 (1 μM). Adherens junctions (AJ) responsible for barrier integrity in the endothelium can also be disturbed by multiple phosphorylations of VE-cadherin, a major AJ protein (27,28), which can lead to disassembly of this protein from AJ complexes and disruption of the endothelial cell-cell contacts. In our experiments, we tested the levels of Tyr 658 -phosphorylated VE-cadherin, which are indicative of AJ instability (29).…”

Hypobaric hypoxia down-regulated junctional protein complex: Implications to vascular leakage

“…[7][8][9] Endothelial paracellular transport of fluid/electrolytes/solutes is normally controlled by intercellular junctional protein complexes, including adherens junction (AJ) and tight junction (TJ). 10,11 A number of proteins are within these junctional complexes, e.g. vascular endothelial (VE)-cadherin (for AJ) and zonula occludens-1 (ZO-1) (for TJ).…”