Neuroimaging in Cardiovascular Disease (NICAD) Network, University of Sheffield, Sheffield, S10 2TN, UK.
Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield Medical School, Beech Hill Road, Sheffield, S10 2RX, UK.
Dis Model Mech. 2019 Sep 25;12(9):dmm039867. doi: 10.1242/dmm.039867.
Diabetes is associated with dysfunction of the neurovascular unit, although the mechanisms of this are incompletely understood and currently no treatment exists to prevent these negative effects. We previously found that the nitric oxide (NO) donor sodium nitroprusside (SNP) prevents the detrimental effect of glucose on neurovascular coupling in zebrafish. We therefore sought to establish the wider effects of glucose exposure on both the neurovascular unit and on behaviour in zebrafish, and the ability of SNP to prevent these. We incubated 4-days post-fertilisation (dpf) zebrafish embryos in 20 mM glucose or mannitol for 5 days until 9 dpf, with or without 0.1 mM SNP co-treatment for 24 h (8-9 dpf), and quantified vascular NO reactivity, vascular mural cell number, expression of a reporter, glial fibrillary acidic protein (GFAP) and transient receptor potential cation channel subfamily V member 4 (TRPV4), as well as spontaneous neuronal activation at 9 dpf, all in the optic tectum. We also assessed the effect on light/dark preference and locomotory characteristics during free-swimming studies. We find that glucose exposure significantly reduced NO reactivity, reporter expression, vascular mural cell number and TRPV4 expression, while significantly increasing spontaneous neuronal activation and GFAP expression (all in the optic tectum). Furthermore, when we examined larval behaviour, we found that glucose exposure significantly altered light/dark preference and high and low speed locomotion while in light. Co-treatment with SNP reversed all these molecular and behavioural effects of glucose exposure. Our findings comprehensively describe the negative effects of glucose exposure on the vascular anatomy, molecular phenotype and function of the optic tectum, and on whole-organism behaviour. We also show that SNP or other NO donors may represent a therapeutic strategy to ameliorate the complications of diabetes on the neurovascular unit.This article has an associated First Person interview with the first author of the paper.
糖尿病与神经血管单元功能障碍有关，尽管其机制尚不完全清楚，目前也没有预防这些负面影响的治疗方法。我们之前发现，一氧化氮（NO）供体硝普钠（SNP）可防止葡萄糖对斑马鱼神经血管耦合的有害影响。因此，我们试图确定葡萄糖暴露对斑马鱼神经血管单元和行为的更广泛影响，以及 SNP 预防这些影响的能力。我们将 4 天孵化（dpf）的斑马鱼胚胎在 20mM 葡萄糖或甘露醇中孵育 5 天，直到 9 dpf，同时或不进行 0.1mM SNP 共同处理 24 小时（8-9 dpf），并在 9 dpf 时定量测量血管 NO 反应性、血管壁细胞数量、报告基因表达、胶质纤维酸性蛋白（GFAP）和瞬时受体电位阳离子通道亚家族 V 成员 4（TRPV4），以及在光感受器板中自发神经元激活，同时也评估了在自由游泳研究中对光/暗偏好和运动特征的影响。我们还发现，葡萄糖暴露显著降低了 NO 反应性、报告基因表达、血管壁细胞数量和 TRPV4 表达，同时显著增加了自发神经元激活和 GFAP 表达（均在光感受器板中）。此外，当我们检查幼虫行为时，我们发现葡萄糖暴露显著改变了在光中时的光/暗偏好以及高速和低速运动。SNP 共同处理逆转了葡萄糖暴露的所有这些分子和行为效应。我们的研究结果全面描述了葡萄糖暴露对光感受器板的血管解剖结构、分子表型和功能以及整个生物体行为的负面影响。我们还表明，SNP 或其他 NO 供体可能代表一种改善神经血管单元糖尿病并发症的治疗策略。本文附有该论文第一作者的第一人称采访。
