Shear Stress and Cellular Crosstalk in Discrete Subaortic Stenosis: Implications for Fibrotic Membrane Formation

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dc.contributor.advisorGrande-Allen, K. Janeen_US
dc.creatorJui, Elysa L.en_US
dc.date.accessioned2024-08-30T16:41:51Zen_US
dc.date.created2024-08en_US
dc.date.issued2024-07-29en_US
dc.date.submittedAugust 2024en_US
dc.date.updated2024-08-30T16:41:51Zen_US
dc.description.abstractDiscrete 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.en_US
dc.embargo.lift2025-02-01en_US
dc.embargo.terms2025-02-01en_US
dc.format.mimetypeapplication/pdfen_US
dc.identifier.citationJui, Elysa L.. Shear Stress and Cellular Crosstalk in Discrete Subaortic Stenosis: Implications for Fibrotic Membrane Formation. (2024). PhD diss., Rice University. https://hdl.handle.net/1911/117802en_US
dc.identifier.urihttps://hdl.handle.net/1911/117802en_US
dc.language.isoengen_US
dc.rightsCopyright is held by the author, unless otherwise indicated. Permission to reuse, publish, or reproduce the work beyond the bounds of fair use or other exemptions to copyright law must be obtained from the copyright holder.en_US
dc.subjectmacrophagesen_US
dc.subjectcardiovascular diseaseen_US
dc.subjectdiscrete subaortic stenosisen_US
dc.subjectshear stressen_US
dc.titleShear Stress and Cellular Crosstalk in Discrete Subaortic Stenosis: Implications for Fibrotic Membrane Formationen_US
dc.typeThesisen_US
dc.type.materialTexten_US
thesis.degree.departmentBioengineeringen_US
thesis.degree.disciplineEngineeringen_US
thesis.degree.grantorRice Universityen_US
thesis.degree.levelDoctoralen_US
thesis.degree.nameDoctor of Philosophyen_US
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