Prenatal Glucocorticoid and Postnatal Blood Pressure

描述（由申请方提供）：实验动物中的大量数据表明，胎儿暴露于糖皮质激素（GC）与长期效应相关，然而，其机制在很大程度上仍未知。在之前的资助期间，我们发现，一个单一的过程中betterone升高动脉血压在成年后代，并与肾单位数量减少25%，但没有肾功能损害，血管反应性的改变与内皮素系统功能障碍兼容。在人类和动物中，产前GC暴露与葡萄糖耐量异常有关。在这个竞争性的继续，我们将测试的假设，内皮素系统的紊乱发挥了核心的致病作用，在长期的心血管和代谢异常目前在成人暴露于产前糖皮质激素。具体而言，我们假设在产前暴露于糖皮质激素的成年后代中：1）内皮素（ET）系统的上调在高血压和葡萄糖耐受不良/胰岛素抵抗的发展中起核心作用; 2）产前糖皮质激素暴露和肥胖之间存在协同作用，其夸大了ET系统的心血管和代谢效应; 3）产前类固醇暴露后，胰岛素抵抗的发展建立了一个正反馈回路，并增强了内皮素系统对动脉血压升高的贡献。我们将测试这些假设与以下具体目标：具体目标1：以确定是否ET系统有助于高血压的发展以下产前糖皮质激素暴露。具体目标二：确定饮食诱导的肥胖是否加重糖皮质激素暴露动物内皮素系统的心血管和代谢效应。具体目标3：确定肥胖/胰岛素抵抗和内皮素系统对产前糖皮质激素暴露的心血管和代谢影响的相互作用。鉴于肥胖症发病率的增加和心血管疾病发育起源的证据越来越多，拟议的研究将确定ET-1系统的作用和产前糖皮质激素暴露与肥胖之间的相互作用。 公共卫生相关性：在人类和动物中，产前糖皮质激素暴露与血压升高和葡萄糖耐量异常有关。 拟议的研究将确定内皮素系统是否在这些异常的发展中起关键作用，以及成年肥胖是否放大了产前暴露于糖皮质激素的人已经存在的变化。 这些信息将有助于在成年后高血压高危人群中建立新的预防干预措施和治疗方法。

DESCRIPTION (provided by applicant): Extensive data in experimental animals indicate that fetal exposure to glucocorticoids (GC) is associated with long term effects, however, the mechanisms remain largely unknown. During the previous funding period we showed that a single course of betamethasone elevates arterial blood pressure in the adult offspring and is associated with a 25% decrease in nephron number, but without an impairment of renal function, and alterations in vascular reactivity compatible with a dysfunction of the endothelin system. In humans and in animals, antenatal GC exposure is associated with glucose tolerance abnormalities. In this competitive continuation we will test the hypothesis that .A derangement in the endothelin system plays a central causative role in the long-term cardiovascular and metabolic abnormalities present in adults exposed antenatally to glucocorticoids.. Specifically we hypothesize that in the adult offspring exposed antenatally to glucocorticoids: 1) The upregulation of the endothelin (ET) system plays a central role in the development of hypertension and glucose intolerance/insulin resistance; 2) There is a synergistic interaction between antenatal glucocorticoid exposure and obesity that exaggerates the cardiovascular and metabolic effects of the ET system; 3) Following antenatal steroid exposure the development of insulin resistance establishes a positive feedback loop and enhances the contribution of the endothelin system to the increase in arterial blood pressure. We will test these hypotheses with the following specific aims: Specific Aim 1: To determine if the ET system contributes to the development of hypertension following antenatal glucocorticoid exposure. Specific Aim 2: To determine if diet-induced obesity exacerbates the cardiovascular and metabolic effects of the endothelin system in glucocorticoid exposed animals. Specific Aim 3: To determine the interactions of obesity/insulin resistance and the endothelin system on the cardiovascular and metabolic effects of antenatal glucocorticoid exposure. Given the increasing incidence of obesity and the mounting evidence for a developmental origin of cardiovascular disease, the studies proposed will determine the role of the ET-1 system and the interaction between antenatal glucocorticoid exposure and obesity. PUBLIC HEALTH RELEVANCE: In humans and in animals, antenatal glucocorticoid exposure is associated with elevations in blood pressure and glucose tolerance abnormalities. The proposed studies will determine if the endothelin system plays a critical role in the development of these abnormalities and if obesity in adulthood magnifies the alterations already present in those exposed prenatally to glucocorticoid. This information will aid in establishing new preventive interventions and therapeutic approaches in populations at risk for developing hypertension in adult life.