The role of oxidative stress in reduced microvascular function after gestational diabetes

项目摘要/摘要 有妊娠期糖尿病(GDM)病史的女性患心血管疾病的风险要高2倍 疾病(CVD)和II型糖尿病(T2 DM)的风险在接下来的十年里增加~7倍 怀孕，但这种关联的根本原因(S)研究相对较少，也缺乏 评估预防性干预以预防或延迟这种疾病发作的试验。微血管功能障碍 先于并促进人类心血管疾病和胰岛素抵抗的发展，通过减少 内皮来源的一氧化氮(NO)和胰岛素介导的NO依赖的血管反应。我们 已经证明，内皮和一氧化氮依赖的扩张在 有妊娠期糖尿病病史的其他健康女性的微血管形成，这种减少部分是通过 氧化应激增加。然而，这种扩张减弱的程度延伸到微血管。 胰岛素介导的反应尚不清楚。因此，在目标1中，我们建议全面审查 氧化应激在其他健康女性微血管内皮细胞胰岛素敏感性降低中的作用 患有妊娠期糖尿病的人。我们的初步数据表明，烟酰胺腺嘌呤二核苷酸磷酸氧化酶 (NADPH氧化酶)显著促进GDM后活性氧的升高，并抑制 NADPH氧化酶改善了这些女性体内内皮细胞和一氧化氮依赖的扩张。因此，在AIM中 2，我们建议全面研究NADPH氧化酶衍生的活性氧物种的作用-- 它们代表了高度特异的治疗和逆转临床前疾病的未来药理学靶点 妊娠期糖尿病后的血管功能障碍会削弱这些女性的微血管内皮功能。二甲双胍 治疗改善高血压高危患者的血管内皮功能和微血管胰岛素敏感性 T2 DM，部分是通过减少氧化应激，这表明二甲双胍治疗在 胰岛素抵抗的发生可能会改善有妊娠期糖尿病病史的女性的微血管内皮反应。 因此，在目标3中，我们建议检查二甲双胍治疗对氧化的急性和慢性影响。 有妊娠期糖尿病病史的健康女性微血管功能障碍的压力中介机制。 总体而言，使用一种创新的人类翻译方法，结合体内药物解剖 血管内皮细胞生化分析与血管功能机制的实验 本文的提出将为1)发育前的早期血管机制提供新的理解 患有妊娠期糖尿病的女性明显的心血管和代谢疾病，以及2)机械地描绘 一种容易获得的、安全的和廉价的治疗方法在手术前恢复微血管功能的疗效 在这一高危女性队列中发病。

PROJECT SUMMARY/ABSTRACT Women with a history of gestational diabetes mellitus (GDM) are at a ~2-fold greater risk for cardiovascular disease (CVD) and a ~7-fold greater risk for type II diabetes mellitus (T2DM) in the decade following pregnancy, but the underlying cause(s) of this association are relatively unstudied, and there is a paucity of trials evaluating preventive intervention to prevent or delay this onset of disease. Microvascular dysfunction precedes and contributes to the development of CVD and insulin resistance in humans, via reductions in endothelial-derived nitric oxide (NO) and insulin-mediated NO-dependent vascular responses, respectively. We have demonstrated that endothelium- and nitric oxide-dependent dilation are attenuated in the microvasculature of otherwise healthy women with a history of GDM and this reduction is mediated, in part, by increased oxidative stress. However, the degree to which this attenuation in dilation extends to microvascular insulin-mediated responses is unknown. Therefore, in aim 1, we propose a comprehensive examination of the role of oxidative stress in attenuated microvascular endothelial insulin sensitivity in otherwise healthy women who have had GDM. Our preliminary data suggest that nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase) contributes significantly to elevated reactive oxygen species after GDM, and that inhibiting NADPH oxidase improves endothelial- and NO-dependent dilation, in vivo in these women. Therefore, in aim 2, we propose a comprehensive examination of the role of NADPH oxidase-derived reactive oxygen species -- which represent a future pharmacological target for the highly specific treatment and reversal of preclinical vascular dysfunction after GDM -- in attenuated microvascular endothelial function in these women. Metformin treatment improves vascular endothelial function and microvascular insulin sensitivity in patients at risk for T2DM, in part through reductions in oxidative stress, suggesting that metformin treatment applied before the onset of insulin resistance may improve microvascular endothelial responses in women with a history of GDM. Therefore, in aim 3, we propose to examine the acute and chronic effects of metformin treatment on oxidative stress-mediated mechanisms of microvascular dysfunction in otherwise healthy women with a history of GDM. Overall, using an innovative translational human approach that combines in vivo pharmaco-dissection of mechanisms of vascular function with the biochemical analysis of biopsied endothelial cells, the experiments proposed herein will provide novel understanding of 1) early vascular mechanisms preceding the development of overt cardiovascular and metabolic disease in women who have had GDM , and 2) mechanistically delineate the efficacy of a readily available, safe, and inexpensive treatment to restore microvascular function before the onset of disease in this high-risk cohort of women.