Lactation, oxytocin and maternal cardiovascular function later in life

1篇摘要 2心血管疾病（CVD）是美国女性死亡的主要原因。女性与男性的不同之处在于 3心血管疾病的发病率和发病时间，并显示心血管疾病和代谢综合征之间有更强的相关性。这 4差异表明，性别特异性因素可能会缓和CVD的潜在病理生理学。我们 5提出哺乳可能是一个这样的妇女特有的因素。多项观察性研究表明， 6母乳喂养减少了母亲以后的心脏代谢疾病;然而， 7对哺乳的有益影响仍然未知。我们的核心假设是高水平的催产素 8在哺乳期产生的保护哺乳期母亲在以后的生活中免受心血管疾病。 我们是第一个报告收缩压和舒张压显著降低的人;脂肪组织更少; 10心脏射血分数、输出量和舒张功能;以及循环心血管 11个风险标志物的小鼠相比，乳酸小鼠没有乳酸。催产素（OXT）是一种神经肽， 12触发子宫收缩，即哺乳期间的乳汁分泌反射，并在母体发育中发挥核心作用。 13行为和社会关系。生理情况下的OXT，如妊娠和哺乳，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水平显著增加， 15的表达。本研究的目的是进一步确定影响 16例哺乳诱导OXT产生后的母体心血管和代谢结局。我们将测试3 17个假设：1）需要哺乳期间的OXT刺激事件-哺乳和母鼠-幼崽相互作用 18的母体在以后的生活中发展出母体心脏保护表型; 2） 19只产后泌乳小鼠是中枢OXT-OXTR系统激活的结果; 在分娩后立即给予非哺乳期小鼠20个外源性OXT将挽救心脏保护性 21表型有或没有预先存在的慢性疾病。目标1是为了模仿奶瓶喂养的情况 22在非母乳喂养的女性;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只条件性基因敲除小鼠（EST-Cre重组酶系统），其在脑中是Oxtr缺陷的。在Aim 3中， 将在肥胖-高血压模型中检验24个假设。纵向体内实验程序将 25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和脂肪组织使用微计算机显微照相术。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，我们的建议将确定哺乳影响产妇的机制， 28健康以后的生活和量化的因果影响母乳喂养对产妇心血管和代谢 29健康我们的研究结果可能会导致进一步的机制探讨哺乳的作用，在产妇 30健康，这可以直接转化为干预措施，以预防妇女心血管疾病。

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.