Effects of life-long hyperlipidaemia on age-dependent development of endothelial dysfunction in humanised dyslipidaemic mice.

Little is known, how life-long hyperlipidaemia affects vascular ageing, before atherosclerosis. Here, we characterise effects of mild, life-long hyperlipidaemia on age-dependent endothelial dysfunction (ED) in humanised dyslipidaemia model of E3L.CETP mice. Vascular function was characterised using magnetic resonance imaging in vivo and wire myograph ex vivo. Plasma endothelial biomarkers and non-targeted proteomics in plasma and aorta were analysed. Early atherosclerosis lesions were occasionally present only in 40-week-old or older E3L.CETP mice. However, age-dependent ED developed earlier, in 14-week-old male and 22-week-old female E3L.CETP mice as compared with 40-week-old female and male C57BL/6J mice. Acetylcholine-induced vasodilation in 8-week-old E3L.CETP, especially female mice, was blocked by catalase and attributed to HO. In 8-week-old female E3L.CETP mice, changes in plasma proteome in response to hyperlipidaemia were modest, while in male mice a number of differentially expressed proteins were identified that were involved in oxidative stress response, inflammation and regulation of metabolic pathways. In contrast, in older E3L.CETP and C57BL/6J mice, either plasma or aortic proteome displayed similar pattern of vascular ageing, dominating over hyperlipidaemia-induced changes. Interestingly, in 48-week-old male but not female E3L.CETP mice, vascular mitochondrial functional response was impaired. Early resilience of hyperlipidaemia-induced detrimental effects in young female E3L.CETP mice on a functional level was associated with a switch in vasodilation mechanism, blunted systemic proteomic response in plasma and slower ED development as compared to male E3L.CETP mice. The results indicate that profile of early vascular response to risk factors in young age may determine level of ED in older age before atherosclerosis development.