Hemodynamic Adaptation of Intercellular Junctions in Human Endothelium

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DESCRIPTION (provided by applicant): The hemodynamic environment appears to be a key regulator of endothelial cell phenotype throughout the circulation. This correlates to the development, localization and progression of atherosclerosis. We are testing this hypothesis with an innovative cell culture model that recreates human hemodynamic shear stress flow patterns from normal and disease regions within the circulation. Data from this work were the first to show that different shear stress patterns modulate the phenotype of the endothelium, including its inflammatory-state, arterial-venous identity, and characteristics of endothelial remodeling. In regions of atherosclerosis, blood flow forces (e.g., shear stress) are distinctly different from regions in arteries free from the disease. Likewise, the endothelium in atherosclerosis-susceptible regions possesses an inflammatory phenotype, higher rate of turnover and increased permeability. Thus, endothelial intercellular junctions might be compromised. There is a paradigm that junctions serve duel functions. The junctions not only serve a structural role in maintaining a permeability barrier, but also a signaling role, by regulating beta- and gamma catenin behavior. Although the structural role is established, the effect of shear stress on the signaling role is less understood and might contribute to differences in endothelial phenotype. Our overall objective is to define a mechanistic link between fluid shear stress and the functional consequences this has on junction stability and endothelial cell phenotype. Flow profiles from normal versus atherosclerosis-prone regions will be compared. Our specific aims are to investigate the effects of shear stress on changes in composition of VE-cadherin and PECAM junction complexes with the catenins. We will also investigate the functional consequences of that remodeling in terms of mechanotransduction, permeability and structural remodeling. Further, we will investigate the effect of shear stress on the signaling, trafficking and transcriptional activity of catenins. Once accomplished, these specific aims will improve understanding of the hemodynamic environment specifically as it relates to heart disease and stroke and lead to new therapeutic targets for this disease.