Program investigators established that glucocorticoid administration to pregnant ewes at 80 d gestation results in elevated blood pressure in offspring as early as 6 months of age, likely as a result of widespread effects on the renin-angiotensin system (RAS). The changes in the RAS resulting from steroid exposure appear specific to each tissue and differ in males and females, but a shift in favor Ang II over Ang-(1-7) is the overall hypothesis to be explored in the renewal application. Adolescents with antenatal steroid exposure (Project 4) show reduced heart rate variability (HRV) without elevated pressure, suggesting altered autonomic function exists in the young human subjects. In Project 3, we show that baroreflex sensitivity (BRS) for control of heart rate and HRV, important indicators of autonomic control and risk factors for higher target organ damage and increased mortality, are impaired preceding the elevation in blood pressure showing direct parallels between the human subjects and the sheep model of fetal programming. In sheep, the BRS impairments are attenuated or reversed acutely with ATi receptor blockade, supporting a role for exaggerated Ang II effects in exposed animals. Protective effects of Ang-(1-7) were shown to be absent or reduced in exposed animals, contributing to the BRS impairment in both males and females. New preliminary studies reveal the increased contribution of Ang II and loss of Ang-(1-7) for control of BRS within the nucleus tractus solitarius (NTS). We propose that elevated expression of Ang II, or decreased Ang-(1-7) or its receptor in the NTS underlies the autonomic dysfunction predisposing to higher blood pressure and target organ damage following antenatal steroid exposure.
Aim 1 : is expression of receptors, processing enzymes for Ang II and Ang-(1-7) formation/ metabolism, or peptide levels in the dorsal medulla including NTS and choroid plexus of the 4th ventricle altered in sheep treated antenatally with betamethasone, prior to or coincident with increased blood pressure, renal or cardiac dysfunction (between 6 wks and 6 months post-natal)? Aim 2: is regulation of the BRS shifted towards Ang II in the NTS of exposed sheep at 6 wks of age? Aim 3: will blockade of Ang-(1-7) receptors in brain 4th ventricle of control sheep impair BRS and initiate an increase in pressure to mimic antenatal steroid exposure? Aim 4: will Ang-(1-7) or an ATi antagonist infusion via 4th ventricle correct the impaired BRS, increased blood pressure and renal manifestations of steroid exposure? The primary objective ofthe Administrative Core is to provide overall administrative support to the program.

Public Health Relevance

The project will provide information on the brain mechanisms involved in the increased susceptibility to autonomic dysfunction in animals exposed to antenatal steroids. Understanding the mechanisms involved in altering the balance of Ang II and Ang-(1-7) will be important to controlling the development of the hypertension and target organ damage related to the antenatal steroid exposure and may provide potential therapeutic interventions for the subsequent cardiovascular problems in human subjects.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Program Projects (P01)
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Special Emphasis Panel (ZHD1)
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Wake Forest University Health Sciences
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Chappell, Mark C; Al Zayadneh, Ebaa M (2017) Angiotensin-(1-7) and the Regulation of Anti-Fibrotic Signaling Pathways. J Cell Signal 2:
Su, Yixin; Bi, Jianli; Pulgar, Victor M et al. (2017) Antenatal betamethasone attenuates the angiotensin-(1-7)-Mas receptor-nitric oxide axis in isolated proximal tubule cells. Am J Physiol Renal Physiol 312:F1056-F1062
South, Andrew M; Nixon, Patricia A; Chappell, Mark C et al. (2017) Antenatal corticosteroids and the renin-angiotensin-aldosterone system in adolescents born preterm. Pediatr Res 81:88-93
Washburn, Lisa K; Nixon, Patricia A; Snively, Beverly M et al. (2017) Antenatal corticosteroids and cardiometabolic outcomes in adolescents born with very low birth weight. Pediatr Res 82:697-703
Massmann, G Angela; Zhang, Jie; Seong, Won Joon et al. (2017) Sex-dependent effects of antenatal glucocorticoids on insulin sensitivity in adult sheep: role of the adipose tissue renin angiotensin system. Am J Physiol Regul Integr Comp Physiol 312:R1029-R1038
Nixon, Patricia A; Washburn, Lisa K; Michael O'Shea, Thomas et al. (2017) Antenatal steroid exposure and heart rate variability in adolescents born with very low birth weight. Pediatr Res 81:57-62
Sigmund, Curt D; Diz, Debra I; Chappell, Mark C (2017) No Brain Renin-Angiotensin System: Déjà vu All Over Again? Hypertension 69:1007-1010
Wilson, Bryan A; Chappell, Mark C (2017) Assessment of the Renin-Angiotensin System in Cellular Organelle: New Arenas for Study in the Mitochondria. Methods Mol Biol 1614:99-121
Wilson, Bryan A; Cruz-Diaz, Nildris; Su, Yixin et al. (2017) Angiotensinogen import in isolated proximal tubules: evidence for mitochondrial trafficking and uptake. Am J Physiol Renal Physiol 312:F879-F886
Chen, Kai; Bi, Jianli; Su, Yixin et al. (2016) Sex-Specific Changes in Renal Angiotensin-Converting Enzyme and Angiotensin-Converting Enzyme 2 Gene Expression and Enzyme Activity at Birth and Over the First Year of Life. Reprod Sci 23:200-10

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