Lactation, oxytocin and maternal cardiovascular function later in life

哺乳期、催产素和母亲晚年心血管功能

基本信息

批准号：
10455709
负责人：
Egle Bytautiene Prewit
金额：
$ 48.35万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10455709
关键词：
ADP-ribosyl Cyclase Adipose tissue Affect Age Behavior Birth Blood Pressure Blood Vessels Body Weight Bottle feeding Brain Brain region Breast Feeding Cardiac Cardiometabolic Disease Cardiovascular Diseases Cardiovascular Physiology Cardiovascular system Cause of Death Cerebellum Child Health Chronic Disease Development Diastolic blood pressure Discipline of Nursing EFRAC Echocardiography Elderly Enterobacteria phage P1 Cre recombinase Epigenetic Process Event Exposure to Feedback Foundations Functional disorder Future Gender Gene Expression Goals Health Heart High Fat Diet Hour Human Hypertension Hypothalamic structure In Vitro Infant Intervention Knockout Mice Lactation Lead Life Link Long-Term Effects Low-Density Lipoproteins Maternal Health Measures Mediating Messenger RNA Metabolic Metabolic syndrome Milk Milk Ejection Modeling Mothers Mus Neurons Neuropeptides Newborn Infant Nipples OXT gene Obesity Observational Study Operative Surgical Procedures Organ Outcome Output Oxytocin Oxytocin Receptor Pattern Peripheral Phenotype Physiological Plasma Play Postpartum Period Pregnancy Procedures Production Prosencephalon Reflex action Regulation Reporting Risk Marker Role Social Behavior Stroke Volume System Testing Therapeutic Time Translating Uterine Contraction Visceral Woman Women&apos s Health antagonist blood pressure reduction cardioprotection conditional knockout design fasting glucose heart function improved in vivo lactation period magnocellular men micrography novel offspring paraventricular nucleus placebo group pregnant prevent pup receptor social suckling

项目摘要

1 ABSTRACT 2 Cardiovascular diseases (CVD) are the leading cause of death in women in the US. Women differ from men in 3 rates and timing of CVD and show a stronger association between CVD and metabolic syndrome. This 4 difference suggests that gender-specific factors may moderate the underlying pathophysiology of CVD. We 5 propose that lactation could be one such women-specific factor. Multiple observational studies have linked 6 breastfeeding with reduced maternal cardiometabolic disease later in life; however, the underlying mechanisms 7 for the beneficial effect of lactation remain unknown. Our central hypothesis is that high levels of oxytocin 8 produced during lactation protect breastfeeding mothers against cardiovascular diseases later in life. 9 We were the first to report significantly lower systolic and diastolic blood pressure; less adipose tissue; better 10 cardiac ejection fraction, output, and diastolic function; and lower concentrations of circulating cardiovascular 11 risk markers in mice that lactated compared to mice that did not lactate. Oxytocin (OXT) is a neuropeptide that 12 triggers uterine contractions, the milk let-down reflex during lactation, and plays a central role in maternal 13 behavior and social affiliation. OXT in physiological situations, such as pregnancy and lactation, induces its 14 own synthesis and release. In our model, we found significantly increased circulating OXT levels and mRNA 15 expression in mice that lactated. The objective of this study is to further define the mechanisms affecting 16 maternal cardiovascular and metabolic outcomes after lactation-induced OXT production. We will test 3 17 hypotheses: 1) OXT-stimulating events during lactation – suckling and maternal-pup interaction – are required 18 for dams to develop maternal cardioprotective phenotype later in life; 2) that higher levels of OXT in 19 postpartum lactated mice is a result from activation of central OXT-OXTR system; 3) administration of 20 exogenous OXT to nonlactating mice in the immediate post-delivery period will rescue the cardioprotective 21 phenotype with or without pre-existing chronic disease. Aim 1 is designed to mimic the bottle-feeding situation 22 in non-breastfeeding women; we will use mice with their nipples surgically removed. In Aim 2 we will use 23 conditional knockout mice (flox-Cre recombinase system) that are Oxtr deficient in the brain. In Aim 3 the 24 hypothesis will be tested in obesity-hypertension model. Longitudinal in vivo experimental procedures will 25 include measuring fasting glucose and blood pressure, and assessing cardiac function with echocardiogram 26 and adipose tissue using micro-computed micrography. In vitro, we will utilize organ explant and vascular 27 reactivity studies. In summary, our proposal will define the mechanisms by which lactation affects maternal 28 health later in life and quantify the causal effect of breastfeeding on maternal cardiovascular and metabolic 29 health. The results of our study may lead to further mechanistic explorations of the role of lactation in maternal 30 health, which could be directly translated into interventions to prevent CVD in women.

1摘要 2种心血管疾病（CVD）是美国女性死亡的主要原因。女人与男人不同 3 CVD的速率和时机，并显示CVD与代谢综合征之间的更强关联。这 4差异表明，性别特异性因素可能会减轻CVD的潜在病理生理。我们 5提议泌乳可能是这样特定女性的一个因素。多个观察性研究已连接 6母乳喂养以后生命后期减少母体心脏代谢疾病；但是，基本机制 7对于泌乳的有益作用仍然未知。我们的中心假设是高水平的催产素哺乳期间产生的8个可保护母亲在生活后期的心血管疾病中免受心血管疾病。 9我们是第一个报告的收缩压和舒张压明显降低的人。脂肪组织较少；更好的 10个心脏射血分数，输出和舒张功能；循环心血管的浓度较低与未裂缝的小鼠相比，乳乳的11个风险标记。催产素（OXT）是一种神经肽 12个触发子宫收缩，哺乳期间的牛奶放松反射，并在母体中起着核心作用 13个行为和社会会员。在身体状况（例如怀孕和泌乳）中的oxt会诱导其 14自己的合成和释放。在我们的模型中，我们发现循环oxt水平和mRNA显着增加 15在小鼠中的表达。这项研究的目的是进一步定义影响的机制 16泌乳引起的OXT产生后的母体心血管和代谢结果。我们将测试3 17个假设：1）需要在泌乳过程中刺激牛的刺激事件 - 哺乳和孕妇相互作用 - 18大坝以后生命以后发展母校心脏保护表型； 2）较高水平的牛 19产后泌乳小鼠是中央OXT-OXTR系统激活的结果。 3）给予 20在交付后立即进行非乳突小鼠的外源性牛将挽救心脏保护 21具有或没有预先存在的慢性疾病的表型。 AIM 1旨在模仿奶瓶喂养情况 22在非胸腔进食妇女中；我们将使用小鼠和手术去除它们的乳头。在AIM 2中，我们将使用 23条有条件的敲除小鼠（Flox-Cre重组酶系统）在大脑中缺乏。在目标3中 24假设将在肥胖 - 亚型模型中进行检验。纵向体内实验程序将 25包括测量空腹葡萄糖和血压，以及使用超声心动图评估心脏功能 26和脂肪组织使用微型计算显微图。在体外，我们将利用器官外植体和血管 27个反应性研究。总而言之，我们的建议将定义泌乳影响母体的机制 28生活中的健康状况，并量化母乳喂养对母亲心血管和代谢的因果关系 29健康。我们的研究结果可能会导致进一步的机械探索泌乳在母体中的作用 30健康可以直接转化为干预措施，以防止女性CVD。