The mechanism by which glucocorticoids program the cardiometabolic impairment is not completely understood. Although one final common pathway may involve the kidney, the decrease in nephron number, by itself, does not explain the elevation in blood pressure. In this project we will address an additional mechanism by which prenatal steroids cause cardiometabolic impairment, i.e., a functional alteration in the local adipose tissue renin angiotensin system (RAS) and that these alterations are amplified by obesity, a "second hit" that tilts the balance towards insulin resistance and further elevations in blood pressure. The working hypothesis is that antenatal steroid exposure has a "programming effect" on white adipose tissue development and function and predisposes the individual for developing insulin resistance and hypertension. We further hypothesize that 1) antenatal steroid exposure alters the function of a local renin-angiotensin system (RAS) within the white adipose tissue, 2) the abnormal adipose tissue RAS function predisposes the individual for developing cardiovascular and metabolic alterations, 3) Obesity exaggerates the functional derangement of adipose tissue, thus increasing the impact antenatal steroid exposure has on cardiovascular and metabolic regulation. Obesity will be induced using a standard ruminant formula, thus fat composition of the diet is removed as a confounding factor. Sheep of both sexes will be randomly allocated to be fed 100% of recommended nutritional allowance or ad libitum for three months. Given the increasing incidence of obesity and the mounting evidence for a developmental origin of cardiovascular disease, the studies proposed will determine if obesity, a modifiable risk factor, has a significant contribution in the development of cardiovascular diseases in animals exposed antenatally to steroids. We will test these hypotheses with the following specific aims:
Specific Aim 1 : To study the effects of antenatal glucocorticoid exposure on the expression of critical components of the RAS and inflammatory mediators in white adipose tissue depots (subcutaneous, omental and perirenal) and the consequences these changes have on adipose tissue function.
Specific Aim 2 : To determine which component(s) of the adipose tissue RAS mediate(s) the cardiometabolic dysregulation in animals exposed antenatally to glucocorticoids.
Specific Aim 3 : To study the mechanism by which superimposed obesity exaggerates the cardiovascular and metabolic abnormalities induced by antenatal steroid exposure.

Public Health Relevance

Antenatal glucocorticoids remain the single alternative to reduce the risk of respiratory distress syndrome in premature newborns. Considering the functional upregulation of the RAS system in steroid-treated animals and the role of the RAS in the regulation of blood pressure in obese and diabetic humans, results from this proposal will pave the way for establishing if obesity in adulthood magnifies the alterations already present in animals exposed prenatally to glucocorticoids.

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Wake Forest University Health Sciences
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Washburn, Lisa K; Brosnihan, K Bridget; Chappell, Mark C et al. (2015) The renin-angiotensin-aldosterone system in adolescent offspring born prematurely to mothers with preeclampsia. J Renin Angiotensin Aldosterone Syst 16:529-38
Marshall, Allyson C; Shaltout, Hossam A; Pirro, Nancy T et al. (2014) Enhanced activity of an angiotensin-(1-7) neuropeptidase in glucocorticoid-induced fetal programming. Peptides 52:74-81
Wilson, Bryan A; Marshall, Allyson C; Alzayadneh, Ebaa M et al. (2014) The ins and outs of angiotensin processing within the kidney. Am J Physiol Regul Integr Comp Physiol 307:R487-9
Chappell, Mark C; Marshall, Allyson C; Alzayadneh, Ebaa M et al. (2014) Update on the Angiotensin converting enzyme 2-Angiotensin (1-7)-MAS receptor axis: fetal programing, sex differences, and intracellular pathways. Front Endocrinol (Lausanne) 4:201
Lee, J-H; Zhang, J; Massmann, G A et al. (2014) Antenatal betamethasone increases vascular reactivity to endothelin-1 by upregulation of CD38/cADPR signaling. J Dev Orig Health Dis 5:56-62
Marshall, Allyson C; Pirro, Nancy T; Rose, James C et al. (2014) Evidence for an angiotensin-(1-7) neuropeptidase expressed in the brain medulla and CSF of sheep. J Neurochem 130:313-23
Bi, Jianli; Contag, Stephen A; Chen, Kai et al. (2014) Sex-specific effect of antenatal betamethasone exposure on renal oxidative stress induced by angiotensins in adult sheep. Am J Physiol Renal Physiol 307:F1013-22
Nixon, P A; Washburn, L K; O'Shea, T M (2013) Antenatal steroid exposure and pulmonary outcomes in adolescents born with very low birth weight. J Perinatol 33:806-10
Washburn, Lisa; Nixon, Patricia; Russell, Gregory et al. (2013) Adiposity in adolescent offspring born prematurely to mothers with preeclampsia. J Pediatr 162:912-7.e1
Marshall, Allyson C; Shaltout, Hossam A; Pirro, Nancy T et al. (2013) Antenatal betamethasone exposure is associated with lower ANG-(1-7) and increased ACE in the CSF of adult sheep. Am J Physiol Regul Integr Comp Physiol 305:R679-88

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