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Molecular mechanisms of endothelial hyperpermeability: implications in inflammation

  • Puneet Kumar (a1), Qiang Shen (a1), Christopher D. Pivetti (a1), Eugene S. Lee (a1), Mack H. Wu (a1) and Sarah Y. Yuan (a1)...

Endothelial hyperpermeability is a significant problem in vascular inflammation associated with trauma, ischaemia–reperfusion injury, sepsis, adult respiratory distress syndrome, diabetes, thrombosis and cancer. An important mechanism underlying this process is increased paracellular leakage of plasma fluid and protein. Inflammatory stimuli such as histamine, thrombin, vascular endothelial growth factor and activated neutrophils can cause dissociation of cell–cell junctions between endothelial cells as well as cytoskeleton contraction, leading to a widened intercellular space that facilitates transendothelial flux. Such structural changes initiate with agonist–receptor binding, followed by activation of intracellular signalling molecules including calcium, protein kinase C, tyrosine kinases, myosin light chain kinase, and small Rho-GTPases; these kinases and GTPases then phosphorylate or alter the conformation of different subcellular components that control cell–cell adhesion, resulting in paracellular hypermeability. Targeting key signalling molecules that mediate endothelial-junction–cytoskeleton dissociation demonstrates a therapeutic potential to improve vascular barrier function during inflammatory injury.

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*Corresponding author: Sarah Yuan, Department of Surgery, University of California Davis Medical Center, 4625 2nd Avenue, Room 3006, Sacramento, CA 95817, USA. Tel: +1 916 703 0422; Fax: +1 916 703 0421; E-mail:
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