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Endothelial cell impact on smooth muscle cell properties: role of hemodynamic forces

Killeen, Maria T. (2009) Endothelial cell impact on smooth muscle cell properties: role of hemodynamic forces. PhD thesis, Dublin City University.

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Abstract

The vascular endothelium is a dynamic cell monolayer located at the interface of the vessel wall and bloodstream, where it regulates the physiological effects of humoral and hemodynamic stimuli on vessel tone and remodelling. Hemodynamic forces are of particular interest and include shear stress, the frictional force generated by blood as it drags against the endothelium, and cyclic strain, transmural pressure due to the pulsatile nature of blood flow. Both forces can profoundly modulate vascular endothelial metabolism and function and, within normal physiological ranges, typically impart an atheroprotective effect which disfavours pathological remodelling of the vessel wall. Changes to arterial wall architecture (i.e. remodelling) are a key feature of vascular diseases (e.g. atherosclerosis) and often stem from disruption of normal blood flow patterns, leading to vascular endothelial dysfunction and dysregulation of the underlying smooth muscle cell layer. The focus of the PhD project was to investigate hemodynamic challenge of vascular endothelial cells impacts smooth muscle cells. In order to assess the hemodynamic challenge of vascular endothelial cells, shear stress and cyclic strain were applied to BAECs. Both forces resulted in morphological realignment of cells along with a clear realignment for the actin cytoskeleton in the direction of flow. Furthermore, ZO-1 localisation also increased at the cell-border. We next investigated how hemodynamic challenge of vascular endothelial cells putatively impacts vascular smooth muscle cell growth properties. Four experimental models were employed namely; laminar shear stress, turbulent shear stress, pulsatile shear stress with co-culture and cyclic strain using in vitro hemodynamic modelling. Laminar shear stress, pulsatile shear stress with co-culture and cyclic strain of endothelial cells resulted in a decrease in BASMC proliferation with a parallel increase in apoptosis. Turbulent shear resulted in the opposite effect caused a slight increase in BASMC proliferation with no effect on apoptosis. This indicated that physiological forces impart an atheroprotective effect. In the hemodynamic models, BAECs and BASMCs were not in physical contact. This suggested that BAECs secreted factor(s) acting directly on the BASMC (or indirectly) on the BAECs were responsible for these effects. As the BAECs and BASMCs were not in physical contact this suggested that BAECs secreted factor(s) acting directly on the BASMC (or indirectly) on the BAECs were responsible for these effects. To investigate the endothelial signalling pathways and effectors putatively mediating these effects specific pharmacological inhibitors were employed. The results revealed that an integrin-Rac1 pathway possibly upstream of NO production may be mediating this endothelial regulatory response under LSS. We investigated the impact of LSS-derived BCM on the expression of cell cycle associated genes within the smooth muscle cells both single gene- and microarray-based RealTime PCR methodologies. Our results highlighted key CDK, cyclins and other cell cycle regulatory proteins. This study confirms the importance of hemodynamic challenge on the endothelium and the putative interactions between endothelial and smooth muscle cells in vascular remodelling.

Item Type:Thesis (PhD)
Date of Award:November 2009
Refereed:No
Supervisor(s):Cummins, Philip
Uncontrolled Keywords:endothelial; smooth muscle; shear stress; cyclic strain; proliferation; signal transduction; vascular biology;
Subjects:Biological Sciences > Biotechnology
DCU Faculties and Centres:DCU Faculties and Schools > Faculty of Science and Health > School of Biotechnology
Use License:This item is licensed under a Creative Commons Attribution-NonCommercial-No Derivative Works 3.0 License. View License
Funders:Science Foundation Ireland
ID Code:4633
Deposited On:12 Nov 2009 14:28 by Phil Cummins. Last Modified 12 Nov 2009 14:28

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