VE-cadherin shedding in vitro and in patients with aortic aneurysm and dissection

Abstract

VE-cadherin (VEC) is a major endothelial adhesion protein, which controls vascular homeostasis. During vascular diseases, VEC can be shed from the endothelial surface by proteases like ADAM10/17, which cleave the extracellular domain of VEC in response to inflammatory cytokines like TNF-α. The resulting, soluble fragments (sVEC) are discussed as a potential marker for endothelial barrier breakdown. However, its pathologic role or its potential as a specific biomarker for aortic diseases is yet unknown. Here we investigated the specificity and linkage of sVEC production with ADAM10/17 and TNF-α, both in vitro and in patients with aortic aneurysms and dissections, comparing the findings with those from patients with carotid stenosis and varicosis. Thereby, the baseline levels of sVEC, TNF-α, ADAM10 and Albumin was measured in clinical plasma samples and cell culture supernatants of human aortic endothelial cells (HAOEC) treated with TNF-α or ADAM10/17 inhibitors. The integrity of HAOEC monolayers was tested by permeability assays using Alexa488-conjugated dextran (10 kDa). Peripheral EDTA plasma samples taken preoperatively from patients ≥ 18 years of age that were diagnosed for aortic dissection (n = 29), aortic aneurysm (n = 76), carotid stenosis (n = 29) and varicose veins (n = 24) were included. In vitro shedding of VEC was induced by TNF-α and depends on ADAM10/17, which led to altered endothelial permeability. Absolute plasma sVEC levels in patients with aortic dissection (3016 ± 1008 ng/mL) and aneurysm (3288 ± 1376 ng/mL) were not statistically significantly different from patients with carotid stenosis (3013 ± 687.6 ng/mL) and varicose veins (3313 ± 1337 ng/mL). Plasma sVEC levels correlated positively with plasma TNF-α (r = 0.5586, p < 0.0001) and ADAM10 (r = 0.7003, p < 0.0001) levels with the highest degree of correlation between ADAM10 and sVEC for chronic aortic dissection (r = 0.7890, p = 0.0013), reflecting TNF-α and ADAM10 dependency of VEC shedding. In summary, VEC shedding and (plasma) sVEC levels are influenced by TNF-α and ADAM10/17 and could play a relevant role in the specific pathophysiological context of aortic diseases.