| Summary: | Ageing is a major risk factor for the development of endothelial dysfunction and cardiovascular disease (CVD). In 2014, CVD was the second most common cause of death in the UK. Clearly, the socio-economic burden of CVD is significant and there is a considerable need for lifestyle modifications, such as nutraceutical supplementation that help ameliorate its severity. Here, we investigated the effects of resveratrol (RV), a polyphenol present in red grapes, berries and peanuts on endothelial function during ageing. There is a murine (Chapters 2-3) and a human (Chapter 4) component to these studies. The aim of the murine component was to establish the vasodilator response during ageing (4 - 26 months of age) of the isolated pressurized mouse femoral artery to pharmacological and mechanical stimuli following incubation with RV. The human component aimed to determine the effects of supplementation with RV on endothelial function and oxygen consumption (VO2) in coronary artery disease (CAD) elderly patients. Hence, the animal study aimed to provide mechanistic insight into the vascular and physiological parameters assessed in humans. In Chapter 2, we describe that the isolated pressurized femoral artery of 26-month old mice does not develop compromised endothelial function when compared to that of 4-month old mice, as reflected by similar levels of dilation in response to acetylcholine (ACh; 10-9 - 10-3 M) and intraluminal flow (5-10 Lmin-1). Despite similar levels of flow-mediated dilation (FMD) of the isolated pressurized femoral artery of young and old mice, there are differences in the role that endothelial factors play in dilation with ageing; addition of L-NG-nitro-L-arginine (LNNA; 100 μM) or apamin (100 nM) + Tram 34 (1 uM) significantly reduced dilation regardless of age. However, addition of indomethacin (10 uM) had no effect on FMD in the young whereas it abolished it in the old. The isolated pressurized mouse femoral artery, regardless of age, shows an initial maximal increase in diameter followed by a sustained plateau phase in response to intraluminal flow. In the presence of flow, the artery auto-regulates its diameter back to pre-constricted levels. Such capacity for auto-regulation is reduced upon addition of LNNA, apamin + Tram 34 or indomethacin. In Chapter 3, we report that RV causes differential effects on ACh-induced and FMD of the isolated pressurized mouse femoral artery; whereas it increases ACh-induced dilation it compromises FMD. RV on its own and in combination with inhibitors of endothelial factors reduce the capacity of the isolated pressurized mouse femoral artery to auto-regulate diameter in the presence of intraluminal flow. The effects of RV on FMD indicate that RV might compromise flow-mediated endothelial mechanotransduction. In Chapter 4, we describe how acute supplementation with high doses of RV (~1 g.day for three days) failed to improve FMD of the brachial artery or VO2 kinetics in elderly CAD patients. Our findings suggest important age-related effects on the mechanisms regulating arterial tone despite preserved degrees of relaxation. Secondly, they raise important questions regarding the insight gained from ex-vivo models. Investigating vasodilation by means of agonists (i.e., ACh) might not provide a comprehensive understanding of the effects of RV on endothelium-dependent dilation. Finally, they question previous in-vitro studies and suggest no significant benefits from acute and high doses of RV on cardiovascular function of older CAD patients.
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