Trends in Cell Biology
ReviewCell adhesion dynamics at endothelial junctions: VE-cadherin as a major player
Introduction
Endothelial cells control the entry of leukocytes into tissue, a function that influences innate and adaptive immunity [1] (Figure 1). In addition, the endothelium forms a barrier that controls vascular permeability (see Glossary) for solutes and blood proteins [2]. Leukocytes and substances can overcome this barrier using two fundamentally different pathways: either a paracellular route requiring the opening of cell contacts or a transcellular route through the body of endothelial cells 3, 4, 5. Transcellular permeability seems to rely on membrane structures, such as vesicular vacuolar organelles (VVOs), which can be induced by permeability-increasing factors, such as vascular endothelial growth factor (VEGF), serotonin and histamine [6]. It has been suggested that extravasating leukocytes migrating via the transcellular route through endothelial cells also use VVOs [7] and other endothelial membrane structures, such as caveolae [8] and membrane invaginations, which engulf the extended podosomes that leukocytes ‘poke’ into the endothelial cell surface [9]. However, quantitative analyses of in vitro transmigration studies indicate that the paracellular route is preferentially used [10], with an increasing contribution of the transcellular pathway under certain conditions, such as overexpression of intercellular adhesion molecule 1 (ICAM-1) [11] and possibly with varying preferences depending on the type of migrating leukocytes and on the conditions of the transmigration assay [12]. Currently, the signaling mechanisms that can upregulate transcellular permeability or transcellular migration of leukocytes in inflammatory settings are not well understood.
The paracellular pathway of leukocyte extravasation requires leukocyte-induced mechanisms that trigger the opening of endothelial cell contacts as well as their closing to avoid leaks and thrombogenic events. This complex process is achieved by a growing number of adhesion and signaling molecules at endothelial cell contacts 3, 4, 13. These membrane proteins seem to function in various steps of the transmigration process 14, 15 and they differ in their relevance for different types of transmigrating leukocytes and their dependence on various cytokines 4, 16.
Several inflammatory mediators and growth factors, such as thrombin, histamine, bradykinin, VEGF, tumor necrosis factor α (TNF-α), lipopolysaccharides (LPS), serotonin and oxidants, can increase vascular permeability, whereas other factors, such as adenosine and the phospholipid sphingosine 1-phosphate (S1P), can stabilize endothelial cell contacts, preventing leaks. Some of these factors, namely serotonin, histamine and VEGF, seem to affect both transcellular [6] and paracellular permeability 17, 18, indicating that both pathways might interact in some ways that are not yet understood. Homeostatic regulation of permeability relies on signaling mechanisms that control transcellular and paracellular pathways. However, most endothelial membrane proteins and signaling mechanisms known to respond to humoral stimuli that induce increases in vascular permeability and leukocyte extravasation function through the paracellular route [2].
From this, it follows that the regulation of endothelial junctions is essential for leukocyte extravasation and immune defense and for many pathophysiological aspects of increased vascular permeability under inflammatory conditions. Reversible destabilization of endothelial junctions by inflammatory mediators can be beneficial because it accelerates the supply with nutrients, oxygen and immunomodulators and assists leukocytes to reach wounded or infected tissue and resolve the damage. However, extended downregulation of endothelial cell contact integrity is of course deleterious; it leads to formation of fluid volume imbalances (edema) and possibly to attachment of platelets to exposed vascular basement membrane. These platelets can deposit additional inflammatory mediators that further increase the leakage, which in turn leads to further accumulation of platelets and, eventually, thrombus formation and occlusion of vessels, resulting in stroke.
The formation and plasticity of endothelial cell contacts is also an essential phenomenon during the development of the blood vessel system during embryogenesis. Various growth factors and receptor systems are involved in this process. Two of them, VEGF-A and angiopoietin-1 (Ang-1) are potent regulators of endothelial cell contacts, with VEGF being a potent enhancer of permeability – originally identified as ‘vascular permeability factor’ (VPF) [19] – and Ang-1 being a potent stabilizer of endothelial cell contacts 20, 21. Recently, new mechanisms have been described that provide novel explanations for how these factors could control endothelial junctions.
Rather than surveying all the known mechanisms involved in the control of endothelial junctions 2, 22, this review focuses on some of the most recently identified novel mechanisms that control the stability and plasticity of endothelial cell contacts and thereby affect vascular permeability and leukocyte extravasation.
Section snippets
Adhesion mechanisms essential for endothelial cell contact stability
The junctional architecture of endothelial cell contacts has been described in excellent reviews 22, 23. In contrast to epithelial cell contacts in which tight and adherens junctions are clearly separated, in endothelial cells these junctions are more intermingled. Vascular endothelial cadherin (VE-cadherin; also known as cadherin 5) is the most important adhesive component of endothelial adherens junctions. Analogous to epithelial cadherin (E-cadherin; also known as cadherin 1), antibodies
Signaling mechanisms that affect endothelial cell contacts
Numerous inflammatory mediators increase vascular permeability by destabilizing endothelial junctions and/or influencing the endothelial contractile apparatus. A complex network of intracellular messengers, such as cyclic adenosine monophosphate (cAMP), Ca2+, phosphoinositol lipids, reactive oxygen and various GTPases (including Cdc42, RhoA, Rac and Rap-1) and their exchange factors, such as guanine-nucleotide-exchange factor-H1 (GEF-H1) and exchange protein activated by cAMP (Epac), have been
Concluding remarks and future perspectives
Much progress has been made recently in identifying novel mechanisms for the regulation of endothelial junctions. Besides the various molecular players that activate the endothelial contractile apparatus at cell contacts, regulation of the cell-adhesive mechanisms at junctions, and especially among those mechanisms involving VE-cadherin, has received much attention. Only a few reports indicate that VE-cadherin function is downregulated by endocytosis [67] or even by degradation [74]. It has
Acknowledgements
We are grateful to Hang Li and Stefan Butz for performing stainings for Figure 1, to Stefan Butz for critically reading the manuscript and to Annette Wintgens for help with Figure 2, Figure 3. This work was supported by the Deutsche Forschungs-gemeinschaft (SFB629) and by the Max Planck Gesellschaft.
Glossary
- Angiogenesis
- the process of blood vessel formation in the embryo, starting from a primitive vascular plexus that is formed in the process of vasculogenesis from primitive endothelial progenitors.
- Diapedesis
- the process of leukocyte transmigration through the blood vessel barrier.
- Extravasation
- the process of leukocyte exit from the vaculature and entry into tissue.
- Vascular basement membrane
- thin protein sheets (50 nm in thickness) that underlie the endothelial cell layer of blood vessels and consist
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