Mechanisms of inflammatory edema

University Of Iowa, Iowa City IA

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Abstract

DESCRIPTION (provided by applicant): Inflammatory edema is a physiologic process that facilitates the transfer of immune competent molecules from vascular spaces to tissues. Histamine is an important mediator of inflammatory edema. Edema caused by histamine is associated with a brief (2 minutes) separation of adjacent endothelial cells by small gaps (1-400 nm). Our work indicates these gaps develop because of a decrease in VE-cadherin binding between adjacent endothelial cells. While the classic cadherins are linked via beta- and alpha-catenin to cortical actin, VE-cadherin has multiple links to the cytoskeleton. It is linked via either beta- or gamma-catenin to alpha-catenin and actin. It is also linked via gamma-cantenin to vimentin. Our data and that of others indicate that histamine decreases the association of VE-cadherin with the cytoskeleton. To understand how histamine alters VE-cadherin based adhesion it is necessary to know if histamine alters binding within the cadherin catenin complex or distal to the catenins. It is also important to know which linkages histamine affects. Our data indicate that VE-cadherin is linked to vimentin as much as it is to actin. Our data also indicate that histamine increase phosphorylation of VE-cadherin, beta- and gamma-catenin and decreases binding alpha-catenin to VE-cadherin. These changes in alpha-catenin binding would decrease the association of VE-cadherin with the cytoskeleton. Phosphorylation of catenins alters binding within the cadherin complex. We have identified kinase and phosphatase activity that is associated with the VE-cadherin complex. The Ras-GAP protein, IQGAP, participates in regulating cadherin-based adhesion by displacing alpha-catenin from the cadherin complex. It is present in the VE-cadherin complex and may be affected by histamine. We want to characterize the different ways VE-cadherin is linked to the cytoskeleton, which of these is affected by histamine, which adaptor and regulatory proteins are associated with which linkages and if their associations change with histamine. We have created a model system to study adhesion of cells transfected with a histamine receptor and cadherin to a cadherin-Fc chimeric protein. We will use this model to determine if histamine alters cadherin-based adhesion due to effects within the cadherin-catenin complex.