Effects of shear stress and cyclic strain on the expression of thrombin receptor gene in human vascular endothelial and smooth muscle cells

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dc.contributor.advisorMcIntire, Larry V.en_US
dc.creatorNguyen, Kytai Truongen_US
dc.date.accessioned2009-06-04T08:39:44Zen_US
dc.date.available2009-06-04T08:39:44Zen_US
dc.date.issued2000en_US
dc.description.abstractMechanical forces such as shear stress and cyclic strain have been shown to regulate expression of many genes that can alter vascular functions such as cell proliferation, leading to the development of vascular diseases including atherosclerosis. Thrombin receptor gene, protease-activated receptor-1 (PAR-1), mediates many important vascular functions such as thrombin-stimulated thrombosis, inflammation, and proliferation of vascular cells; however, the regulation of PAR-1 by mechanical forces has not previously been studied. This thesis investigates effects of shear stress and cyclic strain on gene regulation of PAR-1 in human vascular cells such as endothelial (ECs) and smooth muscle cells (VSMCs) and the molecular mechanisms involved in this regulation. This work finds that shear stress and cyclic strain differentially regulated PAR-1 expression in vascular cells, leading to alterations of cell functions in response to thrombin, and that these processes were mediated through various signaling pathways. Cultured cells were exposed to different levels of shear stress or cyclic strain using the parallel flow plate chamber or uni-axial cyclic strain system. After exposure, PAR-1 mRNA and protein were quantified by Northern blot and flow cytometry, respectively. In addition, inhibitors of various signal pathways such as protein kinases were used to investigate the molecular mechanisms. Arterial shear stresses decreased PAR-1 mRNA and protein both time- and dose-dependently in both macro- and microvascular ECs, leading to attenuation of thrombin-stimulated nitric oxide and endothelin-1 releases. Furthermore, protein kinase C partly mediated shear-reduced PAR-1 expression in both cell types. As in ECs, shear-downregulated PAR-1 expression in VSMCs caused decreases in thrombin-stimulated calcium mobilization and cell proliferation. The transcription mechanism, but not mRNA stability, regulated shear-reduced PAR-1 expression in VSMCs. In contrast to shear stress, high levels of cyclic strain increased PAR-1 expression in VSMCs time-dependently, leading to induction of cell proliferation in response to thrombin, and this process was mediated by reactive oxygen species, possibly through the NADPH pathway. These findings indicate important roles of mechanical forces in regulating vascular functions and thus provide a better understanding of how mechanical factors act to promote vascular diseases.en_US
dc.format.extent138 p.en_US
dc.format.mimetypeapplication/pdfen_US
dc.identifier.callnoTHESIS BIOENG. 2000 NGUYENen_US
dc.identifier.citationNguyen, Kytai Truong. "Effects of shear stress and cyclic strain on the expression of thrombin receptor gene in human vascular endothelial and smooth muscle cells." (2000) Diss., Rice University. <a href="https://hdl.handle.net/1911/19540">https://hdl.handle.net/1911/19540</a>.en_US
dc.identifier.urihttps://hdl.handle.net/1911/19540en_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.subjectCell biologyen_US
dc.subjectBiomedical engineeringen_US
dc.subjectHealth sciencesen_US
dc.subjectMedicineen_US
dc.subjectSurgeryen_US
dc.titleEffects of shear stress and cyclic strain on the expression of thrombin receptor gene in human vascular endothelial and smooth muscle cellsen_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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