Tang, Cheuk Bong; (2002) The molecular mechanisms underlying the development of primary varicose veins. Masters thesis (M.Surg), UCL (University College London).

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Abstract

Of the theories regarding the aetiology of primary varicose veins (VVs), the 'Trendelenburg theory' is perhaps the most widely held, stating that VVs arise after failure of the sapheno-femoral valve (SFV). Although numerous additional factors are thought to contribute to VVs development, their true aetiology remains obscure. It is proposed that a 'molecular' rather than 'physical' mechanism precipitates VVs development, as follows; venous stasis leads to localised venous hypoxia, stimulating the secretion of vascular endothelial growth factor (VEGF) and nitric oxide (NO) which act to increase permeability and dilatation. If the stimulus to dilate remains, but the vein is limited mechanically in the extent of dilatation it can undergo, the continued secretion of VEGF and NO may result in a sequence of molecular events leading ultimately, to a vein more prone to varicosity. Do, therefore, VVs reflect a defect in the balance between the production, release and response to these major agents mediating dilatation. A clinical audit determined the incidence of primary VVs occurring in the presence of an intact SFV. Subsequently, a clinical trial examined the release of VEGF and NO (in patients with VVs, and in control subjects) in response to experimentally- induced venous stasis. Plasma was analysed for VEGF and NO, and peripheral blood mononuclear cells (PBMC's) for VEGF gene expression. Furthermore, to aid in the future investigation of these molecular events, an in vitro model of varicosity was developed. Of all primary VVs assessed here, 43.5% co-presented with a competent SFV. The female:male ratio was 1.92:1, and there was no increase in incidence with age. Peak incidence in females was between 30-60 years, whilst in males this was later, being between 40-70 years. An increased incidence in females with an intact SFV was seen associated more with a 'pre-menopausal' state. Baseline plasma VEGF was equivalent in VVs and controls. Induction of venous stasis stimulated an increase in plasma VEGF in controls (P<0.025), but not in VVs. Plasma NO was not affected by induced venous stasis but however, in all cases, was lower with VVs (all samples, P<0.05). In PBMC's from controls or VVs, baseline VEGF165 and VEGF121 gene expression were similar, and VEGF165 was unaffected by induced venous stasis, in VVs however, there was a 91% increase in VEGF121 gene expression (P<0.08), which was not seen in control subjects. In explants of long saphenous vein in organ culture, a neo-intimal lesion developed in control ('normal') explants by day 7 (P<0.006), through the proliferation and migration of smooth muscle cells (SMC's). In VVs however, although the thickened intima seen at day 0 (P<0.001) remained largely similar, the thickness of the medial layer increased (P<0.001), suggesting SMC proliferation, but without migration. In summary, the loss of release of VEGF, reduced plasma NO and changes in VEGF gene expression, combined with aberrant SMC function, may suggest a mechanism distinct from SFV failure and simple pressure for the aetiology of VVs.

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