Browsing by Author "Jui, Elysa L."

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    Shear Stress and Cellular Crosstalk in Discrete Subaortic Stenosis: Implications for Fibrotic Membrane Formation
    (2024-07-29) Jui, Elysa L.; Grande-Allen, K. Jane
    Discrete subaortic stenosis (DSS) is a pediatric cardiovascular disease characterized by fibrotic membrane formation in the left ventricular outflow tract. This fibrotic growth results in hemodynamic disturbances, increased shear stress, cardiovascular complications, and recurs in 20-30% of patients after surgical removal. Despite its clinical importance, the cellular and molecular mechanisms driving DSS pathogenesis and recurrence remain poorly understood. This dissertation investigates the cellular interactions between macrophages, endothelial cells, and cardiac fibroblasts under shear stress conditions. In my first aim, I investigated the effects of shear stress on macrophage phenotype. Exposure of macrophages to direct shear stress resulted in a time-dependent pro-inflammatory response. In my second aim, I evaluated the effects of shear stress on cellular crosstalk between macrophages and endothelial cells. Cytokines released by sheared macrophages caused endothelial cells to become inflamed and increased their barrier permeability. Conversely, endothelial cells exposed to direct shear stress were not inflamed; however, the cytokines they secreted markedly increased CCL2 expression in macrophages, a potent chemotactic factor. Additionally, CXCL8, a potent neutrophil chemoattractant, was largely upregulated, suggesting a significant role for neutrophil recruitment. Finally, in my last aim, I explored how sheared macrophages and endothelial cells affect cardiac fibroblast activation in a 3D hydrogel model. The results suggest that macrophages and endothelial cells work together to promote cardiac fibroblast activation. These findings highlight the critical role of shear stress-induced macrophage activation and endothelial dysfunction in DSS pathogenesis. This research provides a foundation for developing targeted therapies to prevent fibrotic recurrence and improve outcomes for DSS patients, with future studies focusing on identifying specific signaling pathways involved.