| Summary: | Background: The green tea and pomegranate polyphenols epigallocatechin gallate (EGCG) and ellagic acid (EA) have previously demonstrated anti-atherosclerotic effects and inhibition of VEGFR-2 phosphorylation in cell models. Vascular endothelial growth factor (VEGF) injection into animal models induced atherosclerosis. This thesis aims to investigate whether polyphenols which potently inhibit VEGF-induced VEGFR-2 phosphorylation at physiological concentrations in vitro will be able to inhibit VEGF-induced atherosclerotic development in vivo. Methods: The inhibition of VEGF-induced VEGFR-2 phosphorylation in Human umbilical vein endothelial cells (HUVECs) by EGCG, punicalagin, EA and the urolithins was investigated. The effect of 1.8 g/kg EGCG and EA dietary supplementation on VEGF-induced atherosclerosis was investigated in the ApoE-/- mouse model. Results: EGCG, EA and punicalagin inhibited 50 % VEGF activity, quantified by VEGFR-2 phosphorylation in HUVECs, at 96, 310, and 49 nM. EA metabolism reduced the VEGF inhibitory activity. EGCG and EA significantly inhibited VEGFR-2 phosphorylation at physiological concentrations, predominantly through interactions with the VEGF ligand. 3 weekly intraperitoneal injections of VEGF into mice did not induce atherosclerosis. EGCG and EA dietary supplementation did not affect plaque size but induced small increases in circulating LDL and total cholesterol compared to controls. EGCG and EA injection reduced plaque thickness but not overall size. It was shown that foetal calf serum reduced the polyphenol-mediated inhibition of VEGF activity. Conclusions: The data in this thesis suggest that (1) multiple injections of VEGF does not induce atherosclerotic plaque growth in the ApoE-/- mouse model under the study conditions, (2) a mixture of EGCG and EA had no significant effect on the growth of atherosclerotic plaques when supplemented into the diet of ApoE-/- mice, and (3) serum proteins limit the ability of polyphenols to inhibit VEGFR-2 phosphorylation. These results therefore suggest it is unlikely EGCG and EA reduce atherosclerosis by inhibiting the VEGF ligand in vivo.
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