Glucocorticoids and Programming of the Hypertensive Vascular Phenotype

描述(申请人提供)：在子宫压力下，无论是营养不良还是压力荷尔蒙的使用，都会在以后的生活中导致高血压。我们的宫内食物限制模式与现代社会特别相关，在现代社会，辅助生殖技术的出现导致了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了肥胖和高血压的代谢综合征。使用这个动物模型，我们将确定暴露在高水平的糖皮质激素(GC)下如何诱导血管结构变化，从而促进高血压表型的发展。在初步研究中，我们发现1日龄母亲限食(MFR)的子代主动脉壁GC受体表达增加。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，增加血管暴露于GC会抑制血管VEGF的表达，从而减少血管生成，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，我们已经在MFR子代观察到了这一点，并诱导了升压受体的表达。为了确定GC在血管编程中的核心作用，我们计划在食物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，以及GC代谢酶11β-羟基类固醇脱氢酶1和2的表达和活性。2)采用体内和体外方法，确定母亲阻断GC合成加或不加皮质酮替代对血管血管内皮生长因子表达、血管生成和平滑肌的影响。这项建议将首次在子宫内高水平的血管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建立联系。本项目研究子宫内营养压力导致高血压的发生机制。我们计划通过在怀孕的关键时间点防止应激激素的过度产生来预防高血压的发展和后代血管结构的变化。

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.