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
