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Title: Development of a haemodynamic model system to examine the effects of pressure and strain on human endothelial cells
Author: Wordsworth, Rebecca
Awarding Body: Exeter and Plymouth Peninsula Medical School
Current Institution: Exeter and Plymouth Peninsula Medical School
Date of Award: 2012
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Abstract:
Diabetes is commonly associated with chronic hypertension and evidence suggests that blood pressure control, even in the absence of tight glycemic control, can reduce the risk of diabetic complications in type 1 and type 2 diabetes [87, 88]. Hypertension is associated with raised capillary pressure which could provide a link between high blood pressure and the development of diabetic vascular complications in small blood vessels. Long term changes include stiffening of the blood vessels and, as a result, the cells feel less cyclic strain for a given luminal pressure. This leads to the question; is it altered pressure or strain that is important in reducing the risk of diabetic complications? Many existing models for exposing endothelial cells to mechanical forces in an in-vitro environment alter pressure and strain simultaneously, making it impossible to distinguish between the effects of the two potentially independent stimuli. This distinction is particularly relevant when examining the interaction of haemodynamic forces on microvascular endothelial cells, which are exposed to low hydrostatic pressure but significant strains. Part one describes the development of a haernodynarnlc model system that can evaluate independently the impact of pressure (15 to 35mmHg) and strain (0 to 10%), commensurate with the microvasculature on microvascular endothelial cell function. A perfusion model was developed which allows accurate recording of pressures generated inside the system. A method for applying a continuous sinusoidal cyclical strain of 5-10% is discussed and the model is validated under these conditions for 48 hour periods. Part one also examines the growth and attachment of human endothelial cells in compliant tubing and presents a method for obtaining a confluent layer of cells in the tubing. Part two describes preliminary in vitro studies on the effect of hydrostatic pressure on microvascular endothelial cells and other major environmental factors in type 2 diabetes, e.g. hyperinsulinaemia on the metabolic functions of microvascular and vascular endothelial cells, specifically fatty acid uptake. Preliminary studies indicated that chronic physiological insulin exposure inhibited the uptake of free fatty acids in human umbilical endothelial cells (HUVECs). Furthermore chronic exposure to raised levels of insulin reduced free fatty acid uptake further, which is contrary to studies on other cells lines. Extending the study to microvascular cells, it was also shown that acute exposure to pathophysiological insulin levels stimulated free fatty acid uptake in human brain endothelial cell line (hCMECs).
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.556511  DOI: Not available
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