Section for Integrative Physiology, University of Copenhagen, Copenhagen, Denmark.
Insulin Pharmacology Department, Novo Nordisk A/S, Maaloev, Denmark.
J Physiol. 2017 Aug 15;595(16):5557-5571. doi: 10.1113/JP274623.
Mechanotransduction in endothelial cells is a central mechanism in the regulation of vascular tone and vascular remodelling Mechanotransduction and vascular function may be affected by high sugar levels in plasma because of a resulting increase in oxidative stress and increased levels of advanced glycation end-products (AGE). In healthy young subjects, 2 weeks of daily supplementation with 3 × 75 g of sucrose was found to reduce blood flow in response to passive lower leg movement and in response to 12 W of knee extensor exercise. This vascular impairment was paralleled by up-regulation of platelet endothelial cell adhesion molecule (PECAM)-1, endothelial nitric oxide synthase, NADPH oxidase and Rho family GTPase Rac1 protein expression, an increased basal phosphorylation status of vascular endothelial growth factor receptor 2 and a reduced phosphorylation status of PECAM-1. There were no measurable changes in AGE levels. The findings of the present study demonstrate that daily high sucrose intake markedly affects mechanotransduction proteins and has a detrimental effect on vascular function.
Endothelial mechanotransduction is important for vascular function but alterations and activation of vascular mechanosensory proteins have not been investigated in humans. In endothelial cell culture, simple sugars effectively impair mechanosensor proteins. To study mechanosensor- and vascular function in humans, 12 young healthy male subjects supplemented their diet with 3 × 75 g sucrose day for 14 days in a randomized cross-over design. Before and after the intervention period, the hyperaemic response to passive lower leg movement and active knee extensor exercise was determined by ultrasound doppler. A muscle biopsy was obtained from the thigh muscle before and after acute passive leg movement to allow assessment of protein amounts and the phosphorylation status of mechanosensory proteins and NADPH oxidase. The sucrose intervention led to a reduced flow response to passive movement (by 17 ± 2%) and to 12 W of active exercise (by 9 ± 1%), indicating impaired vascular function. A reduced flow response to passive and active exercise was paralleled by a significant up-regulation of platelet endothelial cell adhesion molecule (PECAM-1), endothelial nitric oxide synthase, NADPH oxidase and the Rho family GTPase Rac1 protein expression in the muscle tissue, as well as an increased basal phosphorylation status of vascular endothelial growth factor receptor 2 and a reduced phosphorylation status of PECAM-1. The phosphorylation status was not acutely altered with passive leg movement. These findings indicate that a regular intake of high levels of sucrose can impair vascular mechanotransduction and increase the oxidative stress potential, and suggest that dietary excessive sugar intake may contribute to the development of vascular disease.
内皮细胞中的力学转导是调节血管张力和血管重塑的核心机制。由于氧化应激增加和晚期糖基化终产物（AGE）水平升高，高血糖可能会影响力学转导和血管功能。在健康的年轻受试者中，发现每天补充 3 次×75g 蔗糖持续 2 周可降低被动小腿运动和 12 瓦特的膝关节伸肌运动的血流反应。这种血管损伤与血小板内皮细胞黏附分子（PECAM-1）、内皮型一氧化氮合酶、NADPH 氧化酶和 Rho 家族 GTPase Rac1 蛋白表达的上调、血管内皮生长因子受体 2 的基础磷酸化状态增加以及 PECAM-1 的磷酸化状态降低相平行。AGE 水平没有可测量的变化。本研究结果表明，每天高蔗糖摄入显著影响力学转导蛋白，并对血管功能产生不利影响。
内皮细胞力学转导对血管功能很重要，但在人类中尚未研究过血管机械感受器蛋白的改变和激活。在内皮细胞培养中，简单糖可有效损害机械传感器蛋白。为了研究人类的机械传感器和血管功能，12 名年轻健康的男性受试者在随机交叉设计的 14 天内每天补充 3 次×75g 蔗糖。在干预前后，通过超声多普勒确定被动小腿运动和主动膝关节伸肌运动的充血反应。在急性被动腿部运动前后从大腿肌肉中获取肌肉活检，以评估机械传感器蛋白和 NADPH 氧化酶的蛋白含量和磷酸化状态。蔗糖干预导致被动运动的血流反应降低（降低 17±2%）和 12 瓦特的主动运动降低（降低 9±1%），表明血管功能受损。被动和主动运动的血流反应降低与肌肉组织中血小板内皮细胞黏附分子（PECAM-1）、内皮型一氧化氮合酶、NADPH 氧化酶和 Rho 家族 GTPase Rac1 蛋白表达的显著上调，以及血管内皮生长因子受体 2 的基础磷酸化状态增加和 PECAM-1 的磷酸化状态降低相平行。磷酸化状态没有在被动腿部运动时被急性改变。这些发现表明，经常摄入高水平的蔗糖会损害血管力学转导并增加氧化应激潜力，并表明饮食中过量的糖摄入可能导致血管疾病的发展。
