Central Effects of Angiotensin‐(1‐7) Treatment on Medullary MAPK and PI3K Pathways of Antenatal Glucocorticoid Exposed Adult Sheep are Sex Dependent

Abstract

Introduction and HypothesisFetal exposure to betamethasone (BMX) that results from the clinical administration of the glucocorticoid agonist to women threatening premature delivery may lead to deleterious long‐term effects on central autonomic regulation. In the adult offspring of pregnant sheep administered antenatal BMX, mean arterial pressure (MAP) is higher and baroreflex sensitivity (BRS) is impaired. These responses are associated with lower brain medullary expression of Angiotensin‐(1‐7) [Ang‐(1‐7)]. Moreover, we observed sex differences in two key signaling pathways implicated in cardiovascular dysfunction and stimulation of oxidative stress in the dorsal brain medulla (DMM) that include higher mitogen‐activated protein kinase (MAPK) in BMX adult male offspring and an attenuated phosphoinositide 3‐kinase (PI3K) pathway in BMX adult female offspring. To establish whether reduced central Ang‐(1‐7) tone contributes to the BMX‐induced cardiovascular effects, we assessed both MAPK and PI3K pathways in the DMM of BMX sheep following 2‐week intracerebroventricular infusion with Ang‐(1‐7) or artificial CSF (aCSF). We hypothesized that in both BMX male and female sheep, Ang‐(1‐7) therapy will correct the observed disturbances in these two pathways.ResultsAlthough presented before, two weeks of Ang‐(1‐7) administration lowered blood pressure and improved baroreflex sensitivity and heart rate variability. In BMX male sheep Ang‐(1‐7) administration was associated with a significant reduction in MAPK activation in the DMM as detected by phosphorylated ERK 1/2 compared to the aCSF‐treated BMX male controls (0.20 ± 0.07 vs 1.04 ± 0.31; p = 0.01), with no change in the PI3K pathway as determined by comparable phosphorylated Akt expression (0.25 ± 0.088 vs 0.36 ± 0.019; p = 0.34). In contrast, BMX female sheep administered Ang‐(1‐7) showed no change in either phosphorylated ERK 1/2 (0.46 ± 0.16 vs 0.70 ± 0.24; p = 0.31) or phosphorylated Akt expression (0.36 ± 0.06 vs 0.33 ± 0.05; p = 0.50) despite that BMX alone reduced PI3K expression.ConclusionCentral administration of Ang‐(1‐7) constitutes a potential therapeutic approach to improve autonomic dysfunction in both BMX exposed sheep; however, distinctly different signaling mechanisms in the DMM of male and female BMX sheep appear to be stimulated by Ang‐(1‐7).Support or Funding InformationHD 047584This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.