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

氧化应激在妊娠糖尿病后微血管功能下降中的作用

基本信息

批准号：
10712433
负责人：
ANNA STANHEWICZ
金额：
$ 60.79万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2028-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10712433
关键词：
Acceleration Acetylcholine Acute Address Animals Attenuated Biochemical Biopsy Blood Vessels Blood capillaries Cardiovascular Diseases Cells Chronic Clinical Clinical Treatment Coupled Cutaneous Data Development Disease Disease Progression Disease Resistance Dissection Endothelial Cells Endothelium Foundations Functional disorder Future Gestational Diabetes Goals Human Insulin Insulin Resistance Intervention Mediating Metabolic Diseases Metformin Microcirculation Microvascular Dysfunction Modeling Molecular NADP NADPH Oxidase Nitric Oxide Non-Insulin-Dependent Diabetes Mellitus Onset of illness Oxidases Oxidative Stress Patients Pregnancy Pregnancy Complications Prevention strategy Public Health Reactive Oxygen Species Recording of previous events Research Risk Role Source Translational Research Vascular Diseases Vascular Endothelium Vasodilation Woman Work attenuation cardiovascular disorder risk clinical translation cohort disorder risk efficacy testing experimental study high risk improved in vivo innovation insulin sensitivity novel pharmacologic post pregnancy pre-clinical prevent preventive intervention programs recruit response risk mitigation therapeutic evaluation therapeutic target treatment strategy vascular bed vascular endothelial dysfunction

项目摘要

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.

项目概要/摘要有妊娠糖尿病 (GDM) 病史的女性患心血管疾病的风险大约高出 2 倍疾病 (CVD) 以及随后十年内患 II 型糖尿病 (T2DM) 的风险增加约 7 倍怀孕，但这种关联的根本原因相对尚未研究，而且缺乏相关研究。评估预防性干预措施以预防或延缓这种疾病发生的试验。微血管功能障碍通过减少胰岛素抵抗，先于并促进人类心血管疾病和胰岛素抵抗的发展分别是内皮源性一氧化氮 (NO) 和胰岛素介导的 NO 依赖性血管反应。我们已经证明内皮和一氧化氮依赖性扩张在有 GDM 病史的其他健康女性的微血管变化，这种减少部分是由以下因素介导的：氧化应激增加。然而，这种扩张衰减延伸到微血管的程度胰岛素介导的反应尚不清楚。因此，在目标 1 中，我们建议对氧化应激在健康女性微血管内皮胰岛素敏感性减弱中的作用患有 GDM 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）对 GDM 后活性氧的升高有显着贡献，并且抑制 NADPH 氧化酶可改善这些女性体内的内皮依赖性和 NO 依赖性扩张。因此，在目标 2、我们建议全面考察NADPH氧化酶衍生的活性氧的作用—— 这代表了高度特异性治疗和逆转临床前疾病的未来药理学目标 GDM 后的血管功能障碍——这些女性的微血管内皮功能减弱。二甲双胍治疗可改善有风险的患者的血管内皮功能和微血管胰岛素敏感性 T2DM，部分是通过减少氧化应激，表明在治疗前应用二甲双胍治疗胰岛素抵抗的发生可能会改善有 GDM 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 GDM 病史的其他健康女性的微血管功能障碍的压力介导机制。总体而言，使用创新的转化人类方法，结合体内药物解剖通过活检内皮细胞的生化分析来了解血管功能的机制，实验本文提出的将为 1) 发育之前的早期血管机制提供新的理解患有 GDM 的女性中明显的心血管和代谢疾病的发生率，以及 2) 机械地描述一种现成的、安全的、廉价的治疗方法在手术前恢复微血管功能的功效在这一高危女性群体中发病。