Glucocorticoids and Programming of the Hypertensive Vascular Phenotype

糖皮质激素和高血压血管表型的编程

• 批准号: 7316053
• 负责人: OMID A. KHORRAM
• 金额: $ 7.08万
• 依托单位: LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-14 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7316053
• 关键词: 11-beta-Hydroxysteroid Dehydrogenases; Address; Adult; Affinity; Angiotensins; Animal Model; Animals; Aorta; Apoptosis; Assisted Reproductive Technology; Birth; Blood Vessels; Cardiovascular Diseases; Corticosterone; Development; Endothelial Cells; Enzymes; Exposure to; Extracellular Matrix; Fetus; Figs - dietary; Food; Functional disorder; Glucocorticoid Receptor; Glucocorticoids; Goals; High Blood Pressure; Hormones; Hypertension; Hypertrophy; Lead; Life; Ligand Binding; Link; Low Birth Weight Infant; Malnutrition; Mesentery; Messenger RNA; Metabolic; Metabolic syndrome; Microcirculation; Microcirculatory Bed; Mineralocorticoid Receptor; Mitotic; Modeling; Neonatal; Newborn Infant; Numbers; Nutritional; Obesity; Pathogenesis; Peripheral; Phenotype; Predisposition; Pregnancy; Prevention; Production; Proteins; Rate; Rattus; Relative (related person); Role; Smooth Muscle; Societies; Starvation; Stress; Structure; Testing; Time; Transcriptional Activation; Up-Regulation; Uterus; Vascular Endothelial Growth Factors; Vascular Smooth Muscle; Vascular resistance; angiogenesis; arteriole; base; day; density; fetal; fetus cell; food restriction; glucocorticoid-induced orphan receptor; in utero; in vivo; muscle hypertrophy; prenatal exposure; prenatal intervention; prevent; programs; receptor; receptor expression

DESCRIPTION (provided by applicant): In utero stress, whether it is undernutrition or administration of stress hormones, induces hypertension later on in life. Our model of in utero food restriction holds particular relevance to modern day society in which the advent of assisted reproductive technologies has led to the birth of increasing number of low birth weight infants many of whom develop the metabolic syndrome with obesity and hypertension as adults. Using this animal model we will determine how exposure to high levels of glucocorticoids (GC) induces structural changes in the blood vessels thereby contributing to the development of the hypertensive phenotype. In preliminary studies we found increased expression of GC receptors in the aorta wall in 1 day old maternal food restricted (MFR) offspring. Furthermore, the expression of Vascular Endothelial Growth Factor (VEGF) was suppressed and there was reduced number of microvascular branching in the mesenteric microcirculation. Based on these finding we have hypothesized that increased vascular exposure to GC results in inhibition of vascular VEGF expression resulting in reduced angiogenesis and therefore increased peripheral vascular resistance. Glucocorticoid exposure also will induce vascular smooth muscle hypertrophy which we have observed in the MFR offspring and induce the expression of receptors for pressors. To establish the central role of GC in programming of the blood vessels we plan on blocking maternal and fetal GC production in the food restriction model with the goal of preventing the development of the hypertensive vascular phenotype. Our specific aims are: 1) compare the vascular expression of GC and mineralocorticoid receptors and their ligand binding affinities, along with expression and activity of the GC metabolizing enzymes 11beta-Hydroxysteroid dehydrogenase 1 and 2. 2) Determine the effect of maternal blockade of GC synthesis with or without corticosterone replacement on vascular VEGF expression, angiogenesis and smooth muscle using an in vivo and ex vivo approach. This proposal will for the first time establish a link between high in utero vascular GC exposure and structural and functional changes of the blood vessels that lead to the development of adult hypertension. This project studies mechanism by which nutritional stress in the womb results in development of hypertension. We plan to prevent development of high blood pressure and changes in the structure of blood vessels in the offspring by preventing the excessive production of stress hormone during a critical time point in pregnancy.

描述（由申请人提供）：在子宫应激中，无论是营养不良还是压力激素的给药，都会在以后的生活中诱导高血压。我们在子宫内食品限制的模型与现代社会特别相关，在这种社会中，辅助生殖技术的出现导致低出生体重婴儿数量增加的诞生，其中许多人以成年人的肥胖和高血压发展了代谢综合征。使用这种动物模型，我们将确定暴露于高水平的糖皮质激素（GC）如何诱导血管中的结构变化，从而有助于高血压表型的发展。在初步研究中，我们发现在1天大的母体食品（MFR）后代中，主动脉壁中GC受体的表达增加。此外，抑制了血管内皮生长因子（VEGF）的表达，肠系膜微循环中微血管分支的数量减少。基于这些发现，我们假设增加血管暴露于GC导致血管VEGF表达抑制，从而导致血管生成减少，从而增加周围血管耐药性。糖皮质激素的暴露还将诱导我们在MFR后代观察到的血管平滑肌肥大，并诱导压力机的受体表达。为了确定GC在血管编程中的核心作用，我们计划在食品限制模型中阻止母体和胎儿GC的产生，目的是防止高血压血管表型的发展。我们的具体目的是：1）比较GC和矿物皮质受体的血管表达及其配体结合相关性，以及GC代谢酶的表达和活性11Beta-Hydroxyteroid脱氢酶1和2。使用体内和离体方法的肌肉。该提案将首次建立在子宫血管GC暴露中的高度与血管结构和功能变化之间的联系，从而导致成人高血压的发展。该项目研究了子宫中营养应激导致高血压发展的机制。我们计划通过防止在怀孕的关键时间点过度产生压力激素，以防止高血压的发展和后代血管结构的变化。