Lactation, Oxytocin and Maternal Cardiovascular Function.

哺乳期、催产素和母亲心血管功能。

• 批准号: 10774048
• 负责人: Egle Bytautiene Prewit
• 金额: $ 9.42万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 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/10774048
• 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; Life; Link; Long-Term Effects; Low-Density Lipoproteins; LoxP-flanked allele; Maternal Health; Measures; Mediating; Messenger RNA; Metabolic; Metabolic syndrome; Milk; Milk Ejection; Modeling; Mothers; Mus; Neurons; Neuropeptides; Newborn Infant; Nipples; 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' 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; post pregnancy; pregnant; prevent; pup; social; suckling; supraoptic nucleus

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 心血管疾病(CVD)是美国女性死亡的主要原因。女性与男性在以下方面有所不同 3心血管疾病的发生率和发生时间，并显示心血管疾病与代谢综合征之间有较强的相关性。这 4性别差异提示，性别差异因素可能影响脑血管病的发病机制。我们 5建议哺乳可能是这种女性特有的因素之一。多项观察性研究表明 母乳喂养减少了母亲晚年的心脏代谢性疾病；然而，潜在的机制 7对于哺乳的有益影响尚不清楚。我们的中心假设是高水平的催产素 在哺乳期间产生的8可以保护哺乳母亲在以后的生活中免受心血管疾病的侵袭。 9我们是第一个报告收缩压和舒张压显著降低的人；脂肪组织减少； 10心脏射血分数、心输出量和舒张期功能；循环心血管浓度较低 哺乳的小鼠与不哺乳的小鼠相比，有11个风险标记物。催产素(OXT)是一种神经肽 12触发子宫收缩，哺乳期间的排乳反射，并在母体中起核心作用 13行为和社会联系。牛在生理情况下，如怀孕和哺乳，会诱导其 14自己合成和发布。在我们的模型中，我们发现循环中的oxt水平和mrna显著增加。 15在哺乳小鼠中的表达。这项研究的目的是进一步确定影响的机制 16哺乳诱导产牛后母体心血管和代谢结果。我们将测试3 17个假设：1)哺乳期的牛刺激事件--哺乳和母婴相互作用--是必需的 18对于母体在生命后期形成心脏保护表型；2)体内较高水平的oxt 19只产后哺乳小鼠是中枢oxt-Oxtr系统激活的结果；3)给药 20只外源性OXT对非哺乳期小鼠的即时产后抢救心脏保护作用 21有或无既往慢性病的表型。Aim 1旨在模拟奶瓶喂养的情况 22在非哺乳妇女中；我们将使用手术切除乳头的小鼠。在《目标2》中，我们将使用 23只大脑中存在OXTR缺陷的条件性基因敲除小鼠(FLOX-Cre重组酶系统)。在目标3中， 24个假说将在肥胖-高血压模型中进行检验。纵向的体内实验程序将 包括测量空腹血糖和血压，以及用超声心动图评估心脏功能。 26和脂肪组织使用微型计算机显微照相。在体外，我们将利用器官外植体和血管 27项反应性研究。总之，我们的建议将定义哺乳影响母亲的机制 28晚年的健康状况，量化母乳喂养对母亲心血管和代谢的因果影响 29健康。我们的研究结果可能导致对哺乳在母体中的作用的进一步的机械性探索。 30健康，这可以直接转化为预防妇女心血管疾病的干预措施。