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Endothelial cell–cell junctions: happy together

Nature Reviews Molecular Cell Biology volume 5, pages 261–270 (2004)Cite this article

Key Points

  • Endothelial cells function as gatekeepers that control the infiltration of leukocytes and plasma proteins into the walls of blood vessels. This control is achieved, to a large extent, through the coordinated opening and closure of cell–cell junctions.

  • Junctions are not only sites of cell–cell attachment but can also function as signalling structures that communicate cell position, limit growth and apoptosis, and regulate vascular homeostasis.

  • Junctional complexes trigger intracellular signals directly, by engaging signalling proteins or growth-factor receptors, or indirectly, by tethering and retaining transcription factors at the cell membrane, thereby limiting their nuclear translocation.

  • Endothelial cells express both adherens and tight junctions, which are formed by different components. In both types of junction, cell–cell adhesion is due to transmembrane adhesive proteins that promote homophilic interactions and form a pericellular zipper-like structure along the cell border.

  • At adherens junctions, endothelial cell adhesion is mediated by vascular endothelial cadherin (VE-cadherin), which is linked to intracellular proteins such as β-catenin, plakoglobin and p120. At tight junctions, adhesion is due to members of the claudin family, which are associated with different intracellular proteins such as zona occludens-1 (ZO1).Other adhesive proteins present at tight junctions are occludin and the members of the junctional adhesion molecule (JAM) family.

  • The organization of adherens and tight junctions requires the nectin–afadin complex. Platelet endothelial cell adhesion molecule (PECAM) is an endothelial junctional component that is located outside adherens and tight junctions.

  • Junctions are required to maintain the integrity of the vessel wall. Modification of the molecular organization and intracellular signalling of junctional proteins might have complex effects on vascular homeostasis.

  • Junctional proteins have an important role in angiogenesis, by modulating cell growth, apoptosis and tubulogenesis. Inactivation of the genes that encode some junctional components prevents normal vascular development in the embryo.

  • Leukocyte infiltration into inflamed regions most frequently occurs through endothelial junctions. The molecular basis of this phenomenon is still largely unknown but it is likely that, on adhesion to inflamed endothelium, leukocytes transfer signals that direct junction rearrangement and promote leukocyte diapedesis.

Abstract

Junctional structures maintain the integrity of the endothelium. Recent studies have shown that, as well as promoting cell–cell adhesion, junctions might transfer intracellular signals that regulate contact-induced inhibition of cell growth, apoptosis, gene expression and new vessel formation. Moreover, modifications of the molecular organization and intracellular signalling of junctional proteins might have complex effects on vascular homeostasis.

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Figure 1: The organization of endothelial cell–cell junctions.
Figure 2: Modulation of VEGFR2 signalling by VE-cadherin.
Figure 3: VEGF signalling in confluent and sparse endothelial cells.
Figure 4: Modulation of junctions in angiogenesis.
Figure 5: Leukocyte diapedesis through endothelial junctions.

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Acknowledgements

E.D. is supported by grants from the European Community, the Italian Association for Cancer Research, Telethon-Italy, the Italian Ministry of Health, the Italian Ministry of University and Research, and the National Research Council Progetto Genomica Funzionale. I would like to thank F. Orsenigo for his help in preparing the figures.

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Authors and Affiliations

  1. Department of Biomolecular and Biotechnological Sciences, School of Sciences, Milan University,

    Elisabetta Dejana

  2. Mario Negri Institute for Pharmacological Research and FIRC Institute of Molecular Oncology, Via Adamello 16, Milan, 20139, Italy

    Elisabetta Dejana

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DATABASES

LocusLink

JAMs

nectin

VEGF

Swiss-Prot

afadin

β-catenin

CDK4

claudin-5

cyclin D1

DEP1

E-cadherin

EGFR

FGFR1

MYC

N-cadherin

PECAM

p27KIP1

S-endo-1

SHP1

SHP2

VE-cadherin

VEGFR2

ZO1

ZO2

ZONAB

FURTHER INFORMATION

Elisabetta Dejana's laboratory

Glossary

THROMBOTIC REACTIONS

The reactions that lead to blood coagulation in the vascular lumen. Endothelial cell damage causes platelet deposition and aggregation, activation of the coagulation system and thrombin generation.

ANGIOGENESIS

The process of forming new vessels by sprouting from pre-existing ones.

DIAPEDESIS

The crossing of endothelial borders by leukocytes, which squeeze between adjacent endothelial cells.

ADHERENS JUNCTION

A cell–cell adhesion complex that contains cadherins and catenins that are attached to cytoplasmic actin filaments.

TIGHT JUNCTION

A circumferential ring at the apex of epithelial cells that seals adjacent cells to one another. Tight junctions regulate solute and ion flux between adjacent epithelial cells.

DESMOSOME

A junctional structure that is formed by transmembrane proteins that are homologous to cadherins and are called desmocollins and desmogleins. These are linked to plakoglobin and desmoplakin and are anchored to intermediate filaments.

CADHERIN

A cell-type-specific calcium-dependent transmembrane adhesion protein. Cadherins promote homophilic binding and are preferentially located at adherens junctions.

CATENIN

A cytoplasmic protein that is directly or indirectly linked to the cytoplasmic tail of cadherins. In this complex, catenins promote the anchoring of cadherins to actin and junction stabilization.

PDZ DOMAIN

(Postsynaptic-density protein of 95 kDa, Discs large and Zona occludens-1). A region that is present in several scaffolding proteins and is named after the founding members of this protein family. PDZ domains bind to specific short amino-acid sequences that are found in several proteins at or outside junctions.

VASCULAR TREE

The complete vascular system, which includes the arteries, veins, capillaries and lymphatic system.

IMMUNOGLOBULIN FAMILY

A large family of proteins that includes antibodies and adhesive transmembrane proteins. Their structure is characterized by 'immunoglobulin loops' that are formed by disulphide bonds.

MAGUKS

A family of proteins that contain membrane-associated guanylate kinase, PDZ and SRC-homology-3 (SH3) domains.

PERICYTE

A cell that is found around capillaries and is related to smooth muscle cells. Pericytes surround the endothelium as single cells. Association with pericytes reduces endothelial apoptosis and stabilizes the vasculature.

FOCAL CONTACTS

Regions of cell attachment to the extracellular matrix. Adhesion receptors and specific cytoskeletal proteins are clustered in these regions.

RHO-FAMILY GTPASES

RAS-related GTPases that are involved in controlling the polymerization of actin.

GUANINE NUCLEOTIDE-EXCHANGE FACTOR

A protein that facilitates the exchange of GDP for GTP in the nucleotide-binding pocket of a GTP-binding protein.

ENDOCARDIUM

The endothelial lining of the cardiac lumen.

VASCULOGENESIS

The formation of vascular structures through the differentiation of endothelial cells from specific progenitors and their subsequent organization into a tubular network.

ANASTOMOSIS

A cross-connection between adjacent channels, tubes, fibres or other parts of a network.

INNATE IMMUNE RESPONSE

This response is crucial during the early phase of host defence against infection by pathogens, before the antigen-specific adaptive immune response is induced.

ADAPTIVE IMMUNE RESPONSE

The antigen-specific response of T and B cells. It includes antibody production and the killing of pathogen-infected cells, and is regulated by cytokines such as interferon-α.

ICAM1

(Intercellular adhesion molecule-1). A member of the immunoglobulin family that is highly expressed on endothelial cell membranes on activation by inflammatory cytokines. It is one of the major adhesive proteins for leukocytes.

EXTRAVASATION

The process by which something is let or forced out from a vessel that naturally contains it.

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Dejana, E. Endothelial cell–cell junctions: happy together. Nat Rev Mol Cell Biol 5, 261–270 (2004). https://doi.org/10.1038/nrm1357

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  • DOI: https://doi.org/10.1038/nrm1357

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