NEUROINFLAMMATION AND SEX-DEPENDENT SIGNALING WITHIN THE DORSAL MEDULLA IN A MODEL OF FETAL PROGRAMMING: EFFECTS OF ANGIOTENSIN-(1-7) SUPPLEMENTATION

Administration of glucocorticoids (GCs) such as betamethasone (BM) for women in jeopardy of preterm labor between 24 and 34 weeks gestation is a highly successful therapeutic intervention resulting in decreasing infant mortality. The immediate effects of BM therapy are beneficial to the offspring, as fetal steroid exposure accelerates lung development and activates the sympathetic nervous system. However, recent longitudinal studies have shown that prenatal exposure to betamethasone caused an increased susceptibility to developing cardiovascular and metabolic disease in adult life. Sheep exposed in utero to BM develop decreased baroreflex sensitivity (BRS) by 6 weeks of age and increased mean arterial pressure (MAP) by 6 months of age. These changes in blood pressure and autonomic function are associated with alterations in components of the brain, renal and circulating renin-angiotensin systems (RAS) that shift the RAS to the pro-hypertensive peptide, angiotensin (Ang) II with lower expression of the antihypertensive peptide, Ang-(1-7). In cerebral spinal fluid (CSF) and dorsomedial medullary tissue both Ang-(1-7) and the Mas receptor are reduced relative to control animals. Our goal was to explore postnatal disturbances in the brain mechanisms associated with the increased susceptibility to autonomic dysfunction in sheep exposed to antenatal BM.This dissertation focuses on the CNS markers of oxidative stress, inflammation and signaling mechanisms that act as possible contributors to BM-induced alterations and the impact of Ang-(1-7) supplementation. We demonstrate that with antenatal BM exposure, there is an increase in microglia and reduced neural nitric oxide synthase (nNOS) expression within the dorsal medial medulla at one year of age. These results are accompanied by sex dependent alterations in signaling pathways: mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K). The supplementation of Ang-(1-7) over a period of 2 weeks in the lateral ventricle recovered cardiometabolic dysfunction, which in male sheep was accompanied by an attenuation of oxidative stress markers and MAPK signaling not seen in females. Collectively, these results reveal potential consequences of dysregulation of the brain RAS resulting in deficiency of Ang-(1-7) that may contribute to elevated sympathetic and reduced parasympathetic tone, associated with impairment in BRS and increased blood pressure. Moreover, my findings reveal sex dependent signaling patterns suggesting distinctly different cellular mechanisms in males versus females underlie similar cardiovascular alternations. In addition, the results highlight the importance of Ang-(1-7) for developing potential therapeutic strategies for observed autonomic dysfunction with BM exposure.

Grantor dc:publisher

Wake Forest University

Year dc:date.issued

2018

Author dc:creator

• Hendricks, Alexa Samiah

Language dc:language.iso

en

Handle dc:identifier.uri

http://hdl.handle.net/10339/93051

OAI identifier oai:identifier

oai:wakespace.lib.wfu.edu:10339/93051