Powell, G.L.; (2010) An examination of VEGF, its receptors and the adherens junction component, β-catenin in the development of primary varicose veins. Masters thesis , UCL (University College London).

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Abstract

Vascular endothelial growth factor (VEGF-A) plays a central role in the maintenance of vascular reactivity and its aberrant control/function is implicated in the development of varicose veins (VVs). However, it is unclear where the problem is; with the vessels ability to produce VEGF-A or indeed an inability to mediate an appropriate response/control to VEGF-A when produced. Here, the patterns of activation of VEGF, its receptors and the adherens junction component, β-catenin were investigated in primary VV. Samples of varicose or control greater saphenous vein (GSV) were divided into segments by anatomical position, descending from the sapheno-femoral junction (SFJ). SFJ and segmental competence were determined from duplex scan. For each segment, patterns of gene transcription (VEGF, VEGF receptors, β-catenin, c-myc and cyclin D1) and β-catenin protein were examined in relation to the underlying venous incompetence. Separately, release of soluble VEGFR1 (s.flt-1, fms like tyrosine kinase receptor 1) was investigated following an induced venous hypertension/stasis. In VVs overall, transcription of all genes were elevated (p<0.001) and in VVs with SFJ incompetence (p<0.001). In competent VV segments (no reflux), transcription of VEGF-A121 (p<0.02), VEGF-A165 (p<0.006) and VEGFR2 (p<0.007) were elevated. Gene transcription was unaffected by segmental position. When the SFJ was functional β-catenin protein was elevated in VVs overall (p<0.06), and increased with descending position from the SFJ (p<0.01); transcription was unaltered. Plasma s.flt- 1 was markedly elevated in VVs (p<0.001), while cuff application induced a rapid (10 minutes, p<0.015) elevation in s.flt-1 in control (54.2%) which was not observed in VVs (5.5%, p>0.1). SFJ incompetence was associated with an elevated in transcription of all genes examined reflecting perhaps, a later stage of disease development. In contrast, elevated transcription of VEGF receptors in segments of competent VV may be an earlier event. Disturbed β-catenin activity (possible due to VEGF) precedes vessel wall compromise in VVs, with elevated β-catenin protein potentially providing a mechanism for vessel wall remodelling. Loss of release of s.flt-1 may be important in the pathogenesis of primary VVs, by potentially mediating the action(s) of VEGF.

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