Soluble VE‐cadherin in rheumatoid arthritis patients correlates with disease activity: Evidence for tumor necrosis factor α–induced VE‐cadherin cleavage

Abstract

Objective. Rheumatoid arthritis (RA) is a chronic, systemic inflammatory disorder that principally attacks synovial joints. However, accelerated atherosclerosis and increased cardiovascular morbidity and mortality are major clinical consequences of endothelial dysfunction in RA patients. Tumor necrosis factor ␣ (TNF␣) is the major mediator of inflammation in RA, related to vascular injury by targeting VE-cadherin, an endothelium-specific adhesion molecule of vital importance for endothelium integrity and angiogenesis. We undertook this study to examine the mechanisms regulating VE-cadherin processing by TNF␣ and their occurrence in RA.Methods. Human umbilical vein endothelial cells were used in primary culture and treated with recombinant TNF␣ to study VE-cadherin cleavage. Cell lysates and conditioned media were analyzed by Western blotting for VE-cadherin cytoplasmic domain and extracellular domain (VE-90) generation, respectively. VE-90 was analyzed at baseline and at the 1-year followup in sera from 63 RA patients (from the Very Early Rheumatoid Arthritis cohort) with disease duration of <6 months.Results. TNF␣ induced a time-dependent shedding of VE-90 in cell media. This effect was prevented by tyrosine kinase inhibitors (genistein and PP2) or by knocking down Src kinase. In contrast, tyrosine phosphatase blockade enhanced VE-cadherin cleavage, confirming the requirement of tyrosine phosphorylation processes. In addition, using the matrix metalloproteinase (MMP) activator APMA and the MMP inhibitor GM6001, we demonstrated that MMPs are involved in TNF␣-induced VE-cadherin cleavage. Of major importance, VE-90 was detected in sera from the 63 RA patients and was positively correlated with the Disease Activity Score at baseline and after 1-year followup.Conclusion. These findings provide the first evidence of VE-cadherin proteolysis upon TNF␣ stimulation and suggest potential clinical relevance of soluble VE-cadherin in management of RA.

Instabilité des jonctions endothéliales : biomarqueurs du remodelage vasculaire

“…Nous avons démontré que le TNF induit le clivage du domaine extracellulaire de la VEcadhérine (sVE) dans des cellules endothéliales, un processus bloqué par des inhibiteurs de tyrosine kinases dont Src, suggérant un lien entre phosphorylation et clivage. De façon très intéressante, le taux de sVE analysé avant traitement dans une cohorte de patients atteints de polyarthrite rhumatoïde (n = 63), est corrélé au score d'activité de la maladie, semblant indiquer que sVE pourrait être proposé comme un nouveau marqueur dans cette affection [9].…”

“…L'hyperplasie du tissu synovial est associée à une angiogenèse. La morbidité vasculaire chez les patients atteints de polyarthrite rhumatoïde est augmentée du fait d'une athérosclérose prématurée, pouvant entraîner des accidents vasculaires cérébraux, des ischémies cérébrales transitoires et des événements coronariens [9]. La découverte de marqueurs prédictifs de l'atteinte vasculaire chez les patients atteints de polyarthrite rhumatoïde pourrait être une aide clinique importante pour guider la prise en charge des patients.…”

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

“…12,13 Over the last 5 years, our group has established that several pathophysiological conditions modify VE-cadherin, either by phosphorylation of tyrosine residues in its intracellular domain or by cleavage of its extracellular domain. [7][8][9][10]14,15 The two processes correlate with dissociation of endothelial cells and increased vascular permeability. These structural modifications to VE-cadherin can result in the protein's extracellular domain (soluble VE-cadherin) becoming detectable in serum from patients with rheumatoid arthritis and angioedema.…”

“…These structural modifications to VE-cadherin can result in the protein's extracellular domain (soluble VE-cadherin) becoming detectable in serum from patients with rheumatoid arthritis and angioedema. 9,10 This could in turn generate candidate biomarkers revealing the presence of activated endothelial cells.…”

“…Disruption of these interactions results in leakage of plasma constituents into the surrounding tissues, leading to edema. 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.…”