The cutaneous microcirculation plays a central role in a range of skin diseases that are characterized by epidermal hyperproliferation or cutaneous inflammation. Many of these diseases are typified by increased vascular permeability, leading to cutaneous edema and exacerbation of disease. In addition, altered vascular organization and/or neovascularization are associated with psoriasis, skin tumorigenesis, and with tissue remodeling during wound healing. Adhesive interactions between adjacent endothelial cells play a central role in both vascular permeability and in the reorganization and growth of endothelial cells during angiogenesis. VE-cadherin is a cell surface adhesion molecule specific to endothelial cells which plays a crucial role in endothelial growth control, vascular barrier function and in morphogenic events associated with angiogenesis. The extracellular domain of VE- cadherin mediates cell to cell contact, whereas the cytoplasmic tail of VE-cadherin functions as a scaffold for a series of proteins termed catenins, which couple VE-cadherin to actin and vimentin cytoskeletal networks. p120 catenin regulation of VE-cadherin is the focus of this proposal. p120- catenin regulates VE-cadherin endocytosis and degradation, and conditional gene ablation experiments indicate that deletion of endothelial p120-catenin leads to vascular malformations and hemorrhage during development. However, the mechanism by which loss of p120 compromises microvascular patterning and vessel integrity is not fully understood. The central hypothesis of this proposal is that p120 and VE-cadherin form a functional unit that is critical for vascular development. Furthermore, we hypothesize that p120 regulates cadherin endocytosis and adhesion strength through distinct molecular mechanisms, and thereby contributes to different aspects of endothelial function through different cellular pathways. These hypotheses will be addressed using a combination of in vitro and in vivo approaches to determine the contribution of p120 to VE-cadherin endocytosis, adhesion strengthening mechanisms, and endothelial tubule formation and proliferation. Completion of these studies will advance our understanding of cadherin based adhesion mechanisms and reveal possible therapeutic targets to regulate angiogenesis and inappropriate vascular regression.
These studies are designed to generate new insights into the basic cellular mechanisms that regulate cell-cell adhesion, and to expose new therapeutic targets for the treatment of skin diseases characterized by alterations in vascular function and inflammation.
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