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Title: The role of inflammatory cytokines and hypoxia in varicose vein wall remodelling
Author: Saunders, Beverley
ISNI:       0000 0004 2691 6375
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2010
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Varicose Veins (VV) affect 10-40% of 30-70 year olds. They have a prominent twisted appearance caused by changes in vein wall thickness. Primary weakening of the vein wall, due to an imbalance in matrix metalloproteinase enzymes (MMP) and their inhibitors (TIMP), is thought to have a major role in homeostasis of extracellular matrix. This could cause dilatation of the vessel wall and dysfunction of the valve cusps resulting in reflux. This could be contributed to by other factors such as an inflammatory response involving cytokinemediated cellular infiltration and/or hypoxia. My study examined mRNA expression in VVs, compared with veins from other sources (VOS), of MMP and TIMP with pro-inflammatory and pro-angiogenic cytokines (TNF-α, IL-1β, IL-6 and VEGF). In parallel I examined expression of hypoxia-regulated transcription factors (HIF). Cell culture was performed on Human Saphenous Vein Endothelial Cells (HSVEC) and HMEC-1 cells exposed to differing degrees of hypoxia. I have shown a significant difference between VVs and VOS in expression of TIMP- 2, -3 and IL-1β. I have demonstrated a significant correlation between VEGF and TIMP-3, TNF-α and MMP-2, MT1-MMP, TIMP-2 and TIMP-3 and IL-1β and MMP-2, MT1-MMP and TIMP-2. This study has also described, for the first time, HIF-1α and HIF-2α expression in VV, and shows that mRNA for both HIFs is significantly reduced in VVs when compared to VOS. HIF-1α significantly correlates with MMP-2, TNF-α and IL-1β, whereas HIF-2α significantly correlates with MT1-MMP and TNF-α. Cell culture studies revealed little difference between different times of hypoxic exposure on mRNA expression of MMP-2, MT1-MMP and TIMP-2 in either cell type. However there was a significant increase in TIMP-3 as the degree of hypoxia increased. These data suggest that alterations in MMP/TIMP, possibly favouring matrix degradation leading to vein wall weakness and dilatation, may be mediated both by changes in inflammatory signals and/or by alterations in oxygen tension.
Supervisor: Davies, Alun Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral