Program invesfigators established that glucocorticoid administration to pregnant ewes at 80 d gestation results in elevated blood pressure in offspring as eariy as 6 months of age, likely as a result of widespread effects on the renin-angiotensin system (RAS). The changes in the RAS resulfing 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 applicafion. Adolescents with antenatal steroid exposure (Project 4) show reduced heart rate variability (HRV) without elevated pressure, suggesfing 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 elevafion 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 tl effects in exposed animals. Protecfive 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 dysfuncfion (between 6 wks and 6 months post-natal)? Aim 2: is regulafion of the BRS shifted towards Ang II in the NTS of exposed sheep at 6 wks of age? Aim 3: will blockade ofAng-(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?

Public Health Relevance

(See Instructions): The project will provide informafion on the brain mechanisms involved in the increased susceptibility to autonomic dysfuncfion 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-DSR-Z (RJ))
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Wake Forest University Health Sciences
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South, Andrew M; Nixon, Patricia A; Chappell, Mark C et al. (2018) Obesity is Associated with Higher Blood Pressure and Higher Levels of Angiotensin II but Lower Angiotensin-(1-7) in Adolescents Born Preterm. J Pediatr :
South, Andrew M; Nixon, Patricia A; Chappell, Mark C et al. (2018) Association between preterm birth and the renin-angiotensin system in adolescence: influence of sex and obesity. J Hypertens 36:2092-2101
Chappell, Mark C; Al Zayadneh, Ebaa M (2017) Angiotensin-(1-7) and the Regulation of Anti-Fibrotic Signaling Pathways. J Cell Signal 2:
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
Sigmund, Curt D; Diz, Debra I; Chappell, Mark C (2017) No Brain Renin-Angiotensin System: Déjà vu All Over Again? Hypertension 69:1007-1010
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
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
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
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

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