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Adama Sidibé

VE-cadherin post-translational modifications: From molecular mechanisms to clinical applications

Published on 14 December 2012


Thesis presented December 14, 2012

Abstract:
The vascular endothelium barrier function is influenced by vascular endothelial cadherin (VE-cadherin) modifications such as its cytoplasmic tail tyrosine phosphorylation and its ecto-domain cleavage (sVE). The work reported herein was divided into two parts:
1- Study of VE-cadherin modifications and the mechanisms underlying these ones in the rheumatoid arthritis context. This work demonstrat​ed that VE-cadherin is a target of TNF
α, a highly important cytokine in rheumatoid arthritis (RA) pathogenesis. We found TNFα to induce sVE shedding in a Src kinase dependent manner, suggesting the involvement of phosphorylation mechanism in this process. In addition, this VE-cadherin cleavage requires matrix metalloproteinase activities such as that of MMP-2. Applying these fundamental data to clinical study showed that sVE was detected in sera of 63 RA patients and its titer was correlated with the disease activity. This finding suggests an obvious interest for assaying sVE in RA therapies.
2- Study of VE-cadherin tyrosine phosphorylation in a context of hormones-regulated angiogenesis during mouse estrous cycle. The results showed VE-cadherin phosphorylation at Y685 that was regulated along mouse estrous cycle allowing to proposing mouse estrous cycle as a physiological model for studying VE-cadherin phosphorylation in vivo. The analysis of VE-cadherin Y685F knock-in mice (VE-Y685F) showed that these mice exhibit a higher vascular permeability in uterus and ovaries and the skin small capillaries compared to wild-type animals. Moreover, VE-Y685F mice presented higher levels of soluble VE-cadherin compared to wild-type counterparts in two induced arthritis model.
Altogether, sVE and VE-cadherin phosphorylation present an array of interests for RA therapies as well as developing new therapeutic tools in RA and other vascular diseases.

Keywords:
Angiogenesis, vascular endothelium, phosphorylation, tyrosine kinase, VE-cadherin, rheumatoid arthritis

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