Prenatal Glucocorticoid and Postnatal Blood Pressure

描述（由申请人提供）：实验动物的大量数据表明，胎儿暴露于糖皮质激素（GC）与长期影响有关，然而，其机制在很大程度上仍然未知。在之前的资助期内，我们发现单疗程的倍他米松会使成年后代的动脉血压升高，并与肾单位数量减少25%有关，但不会损害肾功能，血管反应性改变与内皮素系统功能障碍相一致。在人类和动物中，产前GC暴露与糖耐量异常有关。在这个竞争的延续中，我们将测试假设。内皮素系统的紊乱在产前暴露于糖皮质激素的成人长期心血管和代谢异常中起着中心的致病作用。具体来说，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与肥胖之间存在协同相互作用，夸大了ET系统的心血管和代谢作用；3)在产前类固醇暴露后，胰岛素抵抗的发展建立了一个正反馈循环，并增强了内皮素系统对动脉血压升高的贡献。我们将以以下具体目的检验这些假设：具体目的1：确定ET系统是否有助于产前糖皮质激素暴露后高血压的发展。特定目的2：确定饮食诱导的肥胖是否会加剧糖皮质激素暴露动物内皮素系统的心血管和代谢作用。特定目的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越来越多的证据表明心血管疾病的发育起源，提出的研究将确定ET-1系统的作用以及产前糖皮质激素暴露与肥胖之间的相互作用。

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.