Glucocorticoids and Programming of the Hypertensive Vascular Phenotype

点击翻译按钮获取中文摘要

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.