Taken together, formation of sVE-cadherin is associated and contributes to inflammation-induced breakdown of endothelial barrier functions by inhibition of VE-cadherin binding. The underlying mechanism of VE-cadherin cleavage involves ADAM10 and appears to be of clinical relevance since sVE-cadherin was augmented in patients with severe sepsis.
A clinical diagnostic tool for detection of endothelial barrier disruption in septic patients is not available. We tested whether formation of endothelium‐derived soluble VE‐cadherin fragments (sVE‐cadherin) may be suitable for diagnosis of endothelial barrier breakdown.
Human microvascular endothelial cells were incubated with tumor necrosis factor‐α (TNF‐α) or lipopolysaccharide (LPS), which resulted in endothelial barrier disruption. In temporal correlation significantly increased levels of sVE‐cadherin were detected in cell culture supernatants in western blot and ELISA‐based analyses. This was abrogated when endothelial barrier disruption by TNF‐α or LPS was blocked by application of rolipram. TNF‐α led to reduction of the extracellular domain of VE‐cadherin at the cell borders in immunostaining, whereas total protein amount of VE‐cadherin in endothelial cell lysates remained unaltered. Inhibition of the VE‐cadherin‐specific disintegrin and metalloproteinase ADAM 10 by GI254023X attenuated TNF‐α‐ and LPS‐induced formation of sVE‐cadherin and endothelial barrier disruption.
These data show that formation of sVE‐cadherin is directly associated with endothelial barrier breakdown. The underlying mechanism of VE‐cadherin cleavage involves activation of ADAM10.
Grant Funding Source: Supported by Deutsche Forschungsgemeinschaft (DFG)
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