Hemodynamic Adaptation of Intercelluar Junctions in Human Endothelium

描述（由申请方提供）：血流动力学环境似乎是整个循环中内皮细胞表型的关键调节因子。这与动脉粥样硬化的发展、定位和进展相关。我们正在用一种创新的细胞培养模型来验证这一假设，该模型再现了循环中正常和疾病区域的人体血流动力学剪切应力流动模式。这项工作的数据首次表明，不同的剪切力模式调节内皮细胞的表型，包括其炎症状态，动脉-静脉身份，和内皮重塑的特点。在动脉粥样硬化的区域，血流力（例如，剪切应力）与没有疾病的动脉区域明显不同。同样，动脉粥样硬化易感区域的内皮细胞具有炎症表型、更高的周转率和增加的渗透性。因此，内皮细胞间连接可能受到损害。有一种范式认为连接点具有双重功能。连接不仅在维持渗透性屏障中起结构作用，而且通过调节β-和γ-连环蛋白行为起信号传导作用。虽然建立了结构的作用，剪切应力的信号作用的影响是了解较少，可能有助于内皮细胞表型的差异。我们的总体目标是确定流体剪切应力和功能性后果之间的机械联系，这对连接稳定性和内皮细胞表型。将比较正常与动脉粥样硬化易感区域的血流曲线。我们的具体目标是研究剪切应力对VE-钙粘蛋白和PECAM连接复合物与连环蛋白组成变化的影响。我们还将调查的功能性后果，重塑机械转导，渗透性和结构重塑。此外，我们将研究剪切力对连环蛋白的信号传导、运输和转录活性的影响。一旦实现，这些特定的目标将提高对血液动力学环境的理解，特别是因为它与心脏病和中风有关，并为这种疾病带来新的治疗目标。

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.