Salt appetite & vascular remodeling in fetal origin

说明(申请人提供)：由于怀孕期间的生理和病理生理变化，过量使用盐在孕妇中很常见。高盐饮食与血压升高之间有很强的联系。尽管大量研究表明血管紧张素II(Ang II)及其受体在成人盐摄取和血压控制中发挥重要作用，但关于母亲高盐摄入对胎儿吞咽行为发育的影响、Ang受体亚型AT1、AT2-R和血管稳态以及长期程序对子代心血管调节的影响等方面的信息非常有限。值得注意的是，我们的初步研究已经证明了宫内环境(例如渗透压变化)和激素(例如Ang II)因素在胎儿发育过程中的重要性，以及体液和心血管调节的神经化学机制。有鉴于此，本研究假设：1)孕期母亲盐摄入量可能影响AT1-R/AT2-R，而AT1-R/AT2-R在出生前后的体液平衡和血管收缩中起重要作用；2)在孕期高盐负荷条件下，RAS可能在胎儿及其后代的心血管重构中发挥作用；3)在孕期高盐摄入量条件下，RAS也可能在食盐食欲的发育和规划中发挥关键作用。因此，本研究将确定孕期母体盐负荷对AT1-R、AT2-R和血管收缩功能的影响，以及妊娠期间RAS介导的胎儿和子代心血管对母体盐负荷的影响，以及AT1-R/AT2-R激动剂对年龄依赖性吞咽和程序性食盐量的影响。所获得的数据将为理解孕期母亲高盐对肾素-血管紧张素系统介导的吞咽行为、血管收缩能力和发育来源的食盐量重塑的影响提供重要信息。 项目简介：该项目将确定母亲食盐摄入对子宫内胎儿的急性影响，以及母亲食盐饮食对子代食盐食欲和心血管内环境平衡的慢性影响。这项拟议的研究假设，肾素-血管紧张素系统(RAS)机制在出生前的行为和心血管发育中起作用，母亲摄入盐分可能会对后代造成印记。值得注意的是，在AT2-R占优势的胎儿中，高水合是正常的，而成年人的低水合则伴随着AT1-R的优势。在盐负荷条件下，研究血管紧张素转换酶受体的发育与胎儿体内高水合状态及其反应之间的联系是至关重要的。所获得的结果可能产生关于从主要的AT2-R到主要的AT1-R的转变的重要信息，与出生相关的盐和水平衡的变化有关。此外，体外血管收缩能力研究将确定RAS机制在不同年龄胎儿和子代组织中与盐负荷相关的血管调节机制的作用。总而言之，该项目的重点和综合方法将在预防医学中产生重要信息，涉及对体液量和心血管动态平衡至关重要的RAS控制的发展，以及母亲食盐摄入对子宫内胎儿的急性和慢性影响，以及可能对后代的影响。

DESCRIPTION (provided by applicant): Overuse of salt is common by pregnant women due to physiological and pathophysiological changes during pregnancy. A strong relationship between high salt diet and increased blood pressure (BP) has been demonstrated. Although a number of studies have demonstrated that angiotensin II (ANG II) and its receptors play an important role in salt intake and BP controlling in adults, there is very limited information on the effects of maternal high salt ingestion on the development of fetal swallowing behavior, ANG receptor subtypes-AT1?R and AT2-R, and vascular homeostasis, as well as long-term programming influence on cardiovascular regulation in the offspring. Notably, our preliminary studies have demonstrated the importance of the in utero environmental (e.g., osmotic change) and hormonal (e.g., ANG II) factors on the fetal development of osmoregulatary and neurochemical mechanisms for body fluid and cardiovascular regulation. In light of these, this application hypothesizes: 1) Maternal salt intake during pregnancy may affect AT1-R / AT2-R that are important to body fluid balance and vascular contractility before and after birth; 2) The RAS may play a role in cardiovascular remodeling in the fetus and offspring under conditions of high salt loading during pregnancy; 3) The RAS also may play a critical role in the development and programming of salt appetite under conditions of maternal high salt intake during pregnancy. Therefore, the proposed studies will determine the effects of maternal salt loading on AT1-R and AT2-R and vascular contractility in prenatal and postnatal life, and determine the RAS- mediated cardiovascular changes in the fetus and offspring to maternal salt loading during pregnancy, as well as determine the effect of AT1-R / AT2-R agonists on age-dependent swallowing and programmed salt appetite. The data gained will add important information to understanding of influence of maternal high salt in pregnancy on renin-angiotensin system mediated remolding of swallowing behavior, vascular contractility, and salt appetite in developmental origin. Project Narrative: This project will determine the acute effect of maternal salt intake on the fetus in utero, and the chronic influence of maternal salt diet on the offspring's salt appetite and cardiovascular homeostasis. The proposed study postulates that renin-angiotensin system (RAS) mechanisms are functional in behavioral and cardiovascular development prior to birth, and that maternal salt intake may cause imprinting on the offspring. Notably, high hydration is normal in fetuses associated with a preponderance of AT2-R, while low hydration of adults is accompanied by a preponderance of AT1-R. It is of utmost importance to investigate the extent to which there is any link between the development of the ANG receptors and high hydration status in the fetal body, as well as their responses, under conditions of salt loading. The results gained may generate significant information on the shift from predominantly AT2-R to predominantly AT1-R associated with birth-related change in salt and water balance. In addition, in vitro vascular contractility studies will determine the effect of RAS mechanisms involved in vascular regulation related to salt loading in fetal and offspring tissues at various ages. Together, the focused and integrated approaches of this project will yield important information in preventive medicine, regarding the development of the RAS controlling that is critical for fluid volume and cardiovascular homeostasis, and acute and chronic effects of maternal salt intake on the fetus in utero, and possibly on the imprinting in the offspring.