Alteration of Endothelial Cell Monolayer Integrity Triggers Resynthesis of Vascular Endothelium Cadherin

Abstract

Although cadherins appear to be necessary for proper cell-cell contacts, the physiological role of VE-cadherin (vascular endothelium cadherin) in adult tissue has not been clearly determined. To shed some light on this question, we have disturbed the adhesive function of VE-cadherin in human endothelial cell culture using a polyclonal anti-VE-cadherin antibody. This antibody disrupts confluent endothelial cell monolayers in vitro and transiently generates numerous gaps at cell-cell junctions. The formation of these gaps correlates with a reversible increase in the monolayer permeability. We present evidence that destruction of the homotypic interactions between the extracellular domains of VE-cadherin induces a rapid resynthesis of VE-cadherin, leading to restoration of endothelial cell-cell contacts. The expression of new molecules of VE-cadherin correlates with a modest but significant increase in VE-cadherin mRNA synthesis. Altogether, these results establish a critical role for VE-cadherin in the maintenance and restoration of endothelium integrity.

HIF-2α specifically activates the VE-cadherin promoter independently of hypoxia and in synergy with Ets-1 through two essential ETS-binding sites

“…In vivo, VE-cadherin endocytosis is one of the molecular mechanisms, by which VEGF induces endothelium permeability (Gavard and Gutkind, 2006). Disruption of endothelial contacts by the use of blocking antibodies against VE-cadherin induces endothelium permeability (Gulino et al, 1998) and rapid death (Corada et al, 1999). Further, the N-terminal domain of VE-cadherin is a potential target against tumor vascularization; it is transiently accessible during tumor angiogenesis and blocking with an antibody inhibits tumor growth (May et al, 2005).…”

Auto-antibodies to vascular endothelial cadherin in humans: association with autoimmune diseases

“…In particular, some of these have been shown to disrupt adherens junctions between cultured endothelial cells. 11 Other studies using three different antibodies (CAD5 directed against EC1, BV9 directed against EC3-4, and BV6 directed against EC3) showed that the three antibodies were highly active in several cellular assays, including permeability, calcium switch, and tube formation. These antibodies were also shown to inhibit the protective effect of VEGF on apoptosis.…”

“…4,5 Several antibodies blocking VE-cadherin have been described as potently interfering with the adhesive properties of the protein. 11,16 In several autoimmune diseases, autoantibodies to VE-cadherin (AAVEs) have been described; however, the target epitopes have yet to be identified. The present study was designed to examine whether AAVEs were present in serum from patients with autoimmune diseases.…”

“…6 Accumulating evidence has implicated VE-cadherin in various aspects of vascular biology, including endothelial cell migration, 7 survival, 8 contact-induced growth inhibition, 9 vascular integrity, 10 and, most notably, assembly of endothelial cells into tubular structures. 11 The importance of VE-cadherin in developmental angiogenesis has been demonstrated by the severely impaired vascular assembly observed in VE-cadherin-null mouse embryos. This results in embryonic lethality.…”

“…11 Monoclonal antibodies recognizing various extracellular regions of VE-cadherin have also been developed. These were shown to bind VE-cadherin epitopes specifically exposed during tumor angiogenesis.…”