Glucocorticoids and Programming of the Hypertensive Vascular Phenotype

描述（由申请人提供）：子宫内应激，无论是营养不良还是应激激素，都会在以后的生活中诱发高血压。我们的子宫内食物限制模型与现代社会特别相关，在现代社会中，辅助生殖技术的出现导致越来越多的低出生体重婴儿的出生，其中许多人在成年后患上代谢综合征，伴有肥胖和高血压。使用这种动物模型，我们将确定如何暴露于高水平的糖皮质激素（GC）诱导血管结构的变化，从而有助于高血压表型的发展。在初步研究中，我们发现增加表达GC受体在主动脉壁在1天大的母亲食物限制（MFR）的后代。此外，血管内皮生长因子（VEGF）的表达受到抑制，肠系膜微循环中的微血管分支数量减少。基于这些发现，我们假设血管暴露于GC的增加导致血管VEGF表达的抑制，从而导致血管生成减少，从而增加外周血管阻力。糖皮质激素暴露也会诱导血管平滑肌肥大，我们在MFR后代中观察到了这一点，并诱导升压素受体的表达。为了确定GC在血管编程中的中心作用，我们计划在食物限制模型中阻断母体和胎儿GC的产生，目的是防止高血压血管表型的发展。我们的具体目标是：1）比较GC和盐皮质激素受体的血管表达及其配体结合亲和力，沿着GC代谢酶11 β-羟基类固醇脱氢酶1和2的表达和活性。2)使用体内和离体方法确定母体阻断GC合成（有或无皮质酮替代）对血管VEGF表达、血管生成和平滑肌的影响。这一建议将首次建立子宫内血管GC暴露与导致成人高血压发展的血管结构和功能变化之间的联系。本项目研究子宫内的营养压力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应激激素来防止后代患高血压和血管结构的变化。

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.