Hemodynamic Adaptation of Intercellular Junctions in Human Endothelium

描述（由申请人提供）：血液动力学环境似乎是整个循环中内皮细胞表型的关键调节剂。这与动脉粥样硬化的发生、定位和进展有关。我们正在用一种创新的细胞培养模型来测试这一假设，该模型可以在循环中从正常和疾病区域重现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，不同的剪切应力模式可以调节内皮的表型，包括其炎症状态、动静脉特性和内皮重塑的特征。在动脉粥样硬化区域，血流力（如剪切应力）与无疾病动脉区域明显不同。同样，动脉粥样硬化易感区域的内皮具有炎症表型、更高的周转率和增加的通透性。因此，内皮细胞间连接可能受损。有一种范式认为连接具有双重功能。这些连接不仅在维持通透性屏障中起结构作用，而且还通过调节β -和γ连环蛋白的行为发挥信号作用。虽然结构作用已经确定，但剪切应力对信号传导作用的影响尚不清楚，并可能导致内皮表型的差异。我们的总体目标是确定流体剪切应力和功能后果之间的机制联系，这对连接稳定性和内皮细胞表型有影响。将比较正常和动脉粥样硬化易发区域的血流谱。我们的具体目的是研究剪切应力对ve -钙粘蛋白和PECAM与连环蛋白连接复合物组成变化的影响。我们还将从力学转导、渗透性和结构重塑方面研究这种重塑的功能后果。此外，我们将研究剪切应力对连环蛋白信号传导、转运和转录活性的影响。一旦完成，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靶点。

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.