Neonatal Growth and the Neurodevelopmental Origins of Hypertension

描述(申请人提供)：围产期生长受限是发展为高血压的独立危险因素。一旦了解了导致心血管风险的环境风险因素，就可以确定潜在的机制并制定预防策略。在大鼠模型中，哺乳期间母亲营养不良导致新生儿生长受限、新生儿瘦素缺乏、下丘脑发育改变，以及肥胖相关的对瘦素诱导的厌食症的抵抗。虽然肥胖与抵抗瘦素的代谢效应有关，但新的证据表明，保留的瘦素依赖的交感信号有助于肥胖相关的高血压。为了探索瘦素在高血压神经发育起源中的作用，我们在等基因小鼠中建立了一个新的非干预性模型。在我们庞大的繁育群体中，我们确定了出生体重平均但断奶体重低于10%的小鼠。新生儿生长受限导致严重的新生儿瘦素缺乏，成人下丘脑体积减少，静息性高血压和交感神经张力增加。与对照后代相比，生长受限的小鼠对中枢瘦素注射和心理应激有夸大的升压反应。应激诱发的高血压与下丘脑的激活有关，并被中枢血管紧张素II受体阻断所消除。我们进一步证明：1)中枢应用瘦素可诱导下丘脑肾素血管紧张素系统(RAS)激活，2)在新生儿早期生长受限期间补充瘦素可阻断成人高血压的程序。基于这些数据，我们假设，新生儿生长受限诱导的瘦素缺乏症通过中枢瘦素和血管紧张素II信号的持续增强而导致成人高血压。我们将测试以下假设：i)新生儿生长限制增强了中枢瘦素和血管紧张素II信号，特别是在下丘脑室旁核；ii)新生儿瘦素拮抗剂暴露在正常生长的小鼠中诱导成人高血压；iii)新生儿补充瘦素通过正常化下丘脑生长和中枢血管紧张素II信号来阻止成年高血压的编程。因此，我们的研究试图确定：i)瘦素和RAS在调节动脉血压中的新的相互作用；ii)导致程序性高血压表达的分子途径；iii)引发成人高血压的神经营养因子缺乏；以及iv)一种激素替代疗法，可以很容易地转化为预防程序性高血压。我们的团队致力于了解新生儿生长受限对神经发育的影响，同时我们寻求开发针对可延展的发育窗口的新干预措施，以改变我们对患有终身心血管疾病风险的新生儿的管理。 公共卫生相关性：新生儿生长受限增加了威胁生命的心血管疾病的风险。一旦确定了基本机制，就可以制定预防战略。这项提案旨在确定优化新生儿发育和保护心血管健康的战略。

DESCRIPTION (provided by applicant): Perinatal growth restriction is an independent risk factor for the development of hypertension. Once the environmental risk factors that contribute to cardiovascular risk are understood, underlying mechanisms can be identified and preventative strategies can be developed. In rat models, maternal undernutrition during lactation induces neonatal growth restriction, neonatal leptin deficiency, altered hypothalamic development, and obesity- related resistance to leptin-induced anorexia. While obesity is associated with resistance to the metabolic effects of leptin, emerging evidence suggest preserved leptin-dependent sympathetic signaling contributes to obesity-related hypertension. To explore the role of leptin in the neurodevelopmental origins of hypertension, we developed a novel non-interventional model in isogenic mice. Within our large breeding colony, we identified mice of average birth weight but with a weanling weight below the 10th percentile. Neonatal growth restriction led to profound neonatal leptin deficiency, reduced adult hypothalamic volumes, resting hypertension and increased sympathetic tone. Compared to control offspring, growth restricted mice had exaggerated pressor responses to central leptin administration and psychological stress. The stress-evoked hypertension was associated with hypothalamic activation and was abolished by central angiotensin II receptor blockade. We went on to show 1) central leptin administration elicits hypothalamic renin angiotensin system (RAS) activation and 2) leptin supplementation during incipient neonatal growth restriction blocks the programming of adult hypertension. Based on these data, we hypothesize that neonatal growth restriction-induced leptin deficiency programs adult hypertension through a persistent enhancement in central leptin and angiotensin II signaling. We will test the following hypotheses: I) Neonatal growth restriction enhances central leptin and angiotensin II signaling, particularly within the paraventricular nucleus of the hypothalamus; II) Neonatal leptin antagonist exposure induces adult hypertension in normally grown mice; and III) Neonatal leptin supplementation blocks the programming of adult hypertension by normalizing hypothalamic growth and central angiotensin II signaling. Our studies thus seek to identify: I) a novel interaction between leptin and the RAS in the regulation of arterial blood pressure, II) the molecular pathways that contribute to the expression of programmed hypertension; III) a neurotrophic factor deficiency that triggers adult hypertension, and IV) a hormonal replacement therapy that can be readily translated to the prevention of programmed hypertension. Our team is committed to understanding the effects of neonatal growth restriction on neurodevelopment, as we seek to develop novel interventions targeted to malleable windows of development that could transform our management of neonates at risk of developing life-long cardiovascular disease. PUBLIC HEALTH RELEVANCE: Neonatal growth restriction increases the risk of life-threatening cardiovascular disease. Once the underlying mechanisms are defined, preventative strategies can be developed. This proposal seeks to define strategies to optimize neonatal development and preserve cardiovascular health.