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

• 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
• 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

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.

项目总结/摘要 有妊娠期糖尿病（GDM）病史的女性发生心血管疾病的风险是正常女性的2倍。 糖尿病（CVD）和II型糖尿病（T2 DM）的风险在以下十年中增加约7倍 怀孕，但这种关联的根本原因相对未研究，并且缺乏 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 在人类CVD和胰岛素抵抗的发展之前， 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是衰减的， 有GDM病史的健康女性的微血管减少，这种减少部分是由 增加氧化应激。然而，这种扩张的衰减延伸到微血管的程度， 胰岛素介导的反应是未知的。因此，在目标1中，我们提议全面审查 氧化应激在降低健康女性微血管内皮胰岛素敏感性中的作用 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）显着有助于GDM后活性氧的升高， NADPH氧化酶改善内皮细胞和NO依赖性扩张，在这些妇女体内。因此，在aim 2，我们建议全面检查NADPH氧化酶衍生的活性氧的作用- 其代表了高度特异性治疗和逆转临床前 GDM后的血管功能障碍--在这些妇女中减弱了微血管内皮功能。二甲双 治疗可改善有糖尿病风险患者的血管内皮功能和微血管胰岛素敏感性 T2 DM，部分通过减少氧化应激，表明二甲双胍治疗应用于T2 DM之前， 胰岛素抵抗的发生可能改善有GDM病史的女性微血管内皮反应。 因此，在目标3中，我们建议检查二甲双胍治疗对氧化应激的急性和慢性影响。 有妊娠期糖尿病病史的健康女性中微血管功能障碍的应激介导机制 总的来说，使用一种创新的翻译人类方法，结合体内药物解剖， 血管功能的机制与活检内皮细胞的生化分析，实验 本文提出的方法将提供对1）发育之前的早期血管机制的新理解 明显的心血管和代谢疾病的妇女谁有GDM，和2）机械描绘 一种容易获得的、安全的、廉价的治疗方法在微血管功能恢复之前的有效性。 在这个高风险的女性群体中发病。