Neonatal Growth and the Neurodevelopmental Origins of Hypertension

新生儿生长和高血压的神经发育起源

• 批准号: 8466361
• 负责人: ROBERT D ROGHAIR
• 金额: $ 35.34万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8466361
• 关键词: Adult; Angiotensin II; Angiotensin II Receptor; Angiotensin II Type 1 Receptor Blockers; Angiotensins; Anorexia; Birth Weight; Blood Pressure; Breeding; C57BL/6 Mouse; Cardiovascular Diseases; Cardiovascular system; Commit; Data; Development; Disease susceptibility; Environmental Risk Factor; Fetal Growth Retardation; Growth; Growth and Development function; Health; Hormonal; Human; Human Characteristics; Hypertension; Hypothalamic structure; Infant formula; Infusion procedures; Intervention; Lactation; Leptin; Leptin deficiency; Leptin resistance; Life; Link; Losartan; Malnutrition; Measurement; Metabolic; Modeling; Molecular; Mus; Neonatal; Obesity; Obesity Related Hypertension; Pathway interactions; Perinatal; Phenotype; Plasma; Play; Population; Premature Birth; Premature Infant; Prevention program; Production; Program Development; Psychological Stress; Rattus; Receptor Signaling; Regulation; Renin-Angiotensin System; Replacement Therapy; Resistance; Rest; Risk; Risk Factors; Role; Serum; Signal Transduction; Starvation; Stress; Superoxides; Supplementation; Testing; Third Pregnancy Trimester; Time; Translating; Weight; World Health Organization; base; cardiovascular risk factor; high risk infant; mouse model; neonate; neurodevelopment; neuronal patterning; neurotrophic factor; novel; offspring; paraventricular nucleus; premature; programs; psychologic; public health relevance; pup; response; restraint stress

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.

描述（由申请人提供）：围产期生长受限是发生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，哺乳期母亲营养不良会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力。虽然肥胖与瘦素代谢作用的抵抗有关，但新的证据表明，保留的瘦素依赖性交感神经信号传导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，我们在同基因小鼠中开发了一种新型非干预模型。在我们的大型繁殖群体中，我们发现了平均出生体重但断奶体重低于第 10 个百分位的小鼠。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给药和心理压力有过度的升压反应。应激诱发的高血压与下丘脑激活有关，并可通过中枢血管紧张素 II 受体阻断来消除。我们继续证明：1）中枢瘦素给药可引起下丘脑肾素血管紧张素系统（RAS）激活，2）在新生儿生长受限初期补充瘦素可阻止成人高血压的发生。 基于这些数据，我们假设新生儿生长受限引起的瘦素缺乏通过中枢瘦素和血管紧张素 II 信号传导的持续增强来控制成人高血压。我们将测试以下假设： I) 新生儿生长受限增强中枢瘦素和血管紧张素 II 信号传导，特别是在下丘脑室旁核内； II) 新生期瘦素拮抗剂暴露会在正常生长的小鼠中诱发成年高血压； III) 新生儿瘦素补充剂通过使下丘脑生长和中枢血管紧张素 II 信号传导正常化来阻断成人高血压的编程。 因此，我们的研究旨在确定：I) 瘦素和 RAS 在调节动脉血压方面的新型相互作用，II) 有助于程序性高血压表达的分子途径； III) 神经营养因子缺乏会引发成人高血压，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限制对神经发育的影响，因为我们寻求开发针对可塑性发育窗口的新型干预措施，从而改变我们对面临终生心血管疾病风险的新生儿的管理。