Dermal microvascular endothelial cells play important roles in cutaneous biology, during both normal and pathological settings. An important function of endothelial cells is to provide a selective barrier between the plasma and tissue compartments that regulates the flux of fluid and plasma derived cells into the tissue extracellular space. The loss of endothelial barrier function is associated with inflammation and edema in a number of cutaneous diseases. Adhesive intercellular junctions that form between adjacent endothelial cells are thought to play crucial roles in endothelial barrier function. VE-cadherin is the major adhesion molecule that resides at endothelial cell junctions and plays an important role in endothelial barrier function. In addition, VE-cadherin function is required for the formation of tubules during neovascularization, a process that is important during development, wound healing, and turnorigenesis. VE-cadherin interactions with the cytoskeleton are thought to be fundamental to VE-cadherin flinction in endothelial cells. Plakoglobin and beta-catenin are part of the armadillo (arm) family of proteins and play important roles in attaching cadherins to the cytoskeleton. A newly described protein, termed p007l (p71) is also a member of the arm family and is expressed in endothelial cells where it co-localizes at endothelial intercellular junctions with VE-cadherin. The purpose of this pilot and feasibility study is to characterize the distribution of p7l in endothelial cells both morphologically and biochemically, and to begin an analysis of the binding partners of p71 in endothelial junctions. In addition, the feasibility of a model for neovascularization will also be tested. The endothelial-specific promoter from the VE-cadherin gene 'will be used to drive the expression of endothelial functional proteins in developing embryoid bodies in vitro. It is predicted that the arm proteins couple VE-cadherin to the cytoskeleton, that this linkage is needed for VE-cadherin function, and that disrupting this linkage will compromise the ability of endothelial cells to organize into new vessels. These studies are designed to provide the basis for an individual research proposal focusing on the role of arm proteins in dermal microvascular endothelial barrier function and neovascularization.
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