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Regulation of ensothelial barrier properties through activation of Rho family GTPases

Objective

Endothelium is a dynamic orhan with secretory and immunological functions that plays a key role in homeostasis, thrombosis and inflammation. Endothelial cells create a continuous monolayer lining blood vessels, semi-permeable to macromolecules, salutes and liquid, highly regulated by blood-born mediators.

The endothelial barrier function is critically dependent on the integrity of cell-cell adhesion structures, especially the tight junctions and the adherens junctions (AJ). Endothelial AJ associates with acti n cytoskeleton and link neighbouring cells through the transmembrane VE-cadherin (Vascular Endothelial cadherin), the molecule that constitutes the backbone of AJ. Studies have shown that disassembly of AJ is an essential feature of the increased endothelial permeability response.

Endothelial AJ are dynamic structures which respond to inflammatory mediators and thus modify their adhesion strength and alter endothelial barrier function. Cell-cell adhesion strength is regulated by: a) the extracellular cadherin repeats domain, and b) the cadherin cytoplasmic domain where p120- and b-catenins bind.

These molecules function as essential linkers between cadherin and the actin cytoskeleton, which is requirement for strong cell-cell adhesion. Proinflammatory mediators such as thrombin, histamine and bradykinin activate their endothelial surface receptors and induce increased endothelial permeability responses through second messengers activation. In such cases endothelial cell-cell adhesion mediated by AJ is modulate d from strong to weak.

The proposed studies aim to explore mechanisms responsible for reversal of the permeability increase and barrier recovery. We will study how endothelial adhesive structures and the associated cytoskeleton regulate barrier function. Specifically how adherens junctions participate in the reformation of endothelial junctions after the administration of pro-inflammatory agents.

Call for proposal

FP6-2002-MOBILITY-12
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Funding Scheme

IRG - Marie Curie actions-International re-integration grants

Coordinator

UNIVERSITY OF IOANNINA
Address
Panepistimioupoli Ioanninon
Ioannina
Greece