Deficiency in Angiotensin-(1-7) Alters Signaling Pathways Linked to ROS and NO in the Brain

Wake Forest University Health Sciences, Winston-Salem NC

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Abstract

Project Summary Glucocorticoids (GCs) including betamethasone (BM) are routine therapy administered to women at risk of early preterm labor to facilitate fetal lung development and reduce infant mortality rates. However, fetal steroid exposure may lead to negative long term consequences for autonomic regulation. In a sheep model of fetal programming, BM-exposed (BMX) adult offspring exhibit elevated mean arterial pressure (MAP), decreased baroreflex sensitivity (BRS) for control of heart rate and insulin resistance accompanied by dysregulation of the brain, renal and circulating renin-angiotensin system (RAS).In the brain solitary tract nucleus of the dorsal medulla and cerebrospinal fluid from 4th ventricle, a major area of autonomic integration, there is a shift towards the sympathetic activator angiotensin II (Ang II) and actions through the AT1 receptor that oppose the beneficial actions of angiotensin-(1-7) [Ang-(1-7)] at the Mas receptor for BRS regulation in both sexes. The signaling mechanisms and extent of alterations in oxidative stress and/or inflammatory pathway within the brain in animals given BMX has yet to be established. My dissertation has established consequences of fetal exposure to GCs on intracellular signaling within the adult brain medulla at 12 months of age in particular, two key pathways that are prominent in the actions of angiotensins, insulin and leptin: mitogen activated kinase pathway (MAPK) and phosphoinositide 3-kinase pathway (PI3K). My data shows that sex-specific mal-adaptive changes in these two signaling pathways (increased phosphorylated ERK1/2 in males; decreased phosphorylated Akt and GSK-3? in females) within cardiovascular centers of the brain accompanies the improper processing of Ang peptides, which in turn may impact oxidative stress, inflammation and sympathetic outflow. I then tested the hypothesis that replacement of Ang-(1-7) via intracerebroventricular infusion in 4-5 month old BMX sheep, that already shown to prevent the increase in blood pressure and improve baroreflex sensitivity, reverse programming effects on signaling, oxidative stress and inflammation, providing insight into mechanisms of Ang-(1-7) actions. Preliminary data shows that replacement of Ang-(1-7) in male BMX sheep at this early age significantly lowers phosphorylated protein expression of ERK1/2 compared to BMX males given aCSF. There is a trend for an inverse correlation of the BRS and ERK1/2 and a significant inverse correlation of Mas receptor expression and blood pressure. My future studies will provide information on alterations in signaling pathways and their downstream effector mechanisms (reactive oxygen species, nitric oxide and inflammation) resulting from BMX-induced down-regulation of the Ang-(1-7)-Mas receptor axis that may lead to a host of neural dysregulation and disease; indeed, the MAPK and PI3K pathway has been implicated in Alzheimer's disease plaque formation. My future interest is to investigate in the human population the role of RAS and cardiometabolic function on cognitive decline. With a more epidemiological and public health approach I hope to contribute to better understanding of factors related to diseases of aging.