title: Fetal betamethasone exposure attenuates angiotensin-(1-7)-Mas receptor expression in the dorsal medulla of adult sheep.
abstract: Glucocorticoids including betamethasone (BM) are routinely administered to women entering into early preterm labor to facilitate fetal lung development and decrease infant mortality; however, fetal steroid exposure may lead to deleterious long term consequences. In a sheep model of fetal programming, BM-exposed (BMX) offspring exhibit elevated mean arterial pressure (MAP) and decreased baroreflex sensitivity (BRS) for control of heart rate by 0.5-years of age associated with changes in the circulating and renal renin-angiotensin systems (RAS). In the brain solitary tract nucleus, angiotensin (Ang) II actions through the AT1 receptor oppose the beneficial actions of Ang-(1-7) at the Mas receptor for BRS regulation. Therefore, we examined Ang peptides, angiotensinogen (Aogen), and receptor expression in this brain region of exposed and control offspring of 0.5- and 1.8-years of age. Mas protein expression was significantly lower (>40%) in the dorsal medulla of BMX animals at both ages; however, AT1 receptor expression was not changed. BMX offspring exhibited a higher ratio of Ang II to Ang-(1-7) (2.30±0.36 versus 0.99±0.28; p<0.01) and Ang II to Ang I at 0.5-years. Although total Aogen was unchanged, Ang I-intact Aogen was lower in 0.5-year BMX animals (0.78±0.06 vs. 1.94±0.41; p<0.05) suggesting a greater degree of enzymatic processing of the precursor protein in exposed animals. We conclude that in utero BM exposure promotes an imbalance in the central RAS pathways of Ang II and Ang-(1-7) that may contribute to the elevated MAP and lower BRS in this model.
authors.affiliation: Hypertension and Vascular Research Center, Wake Forest School of Medicine, Winston Salem, NC, United States.
authors.forename: Allyson C
authors.initials: AC
authors.lastname: Marshall
authors.forename: Hossam A
authors.initials: HA
authors.lastname: Shaltout
authors.forename: Manisha
authors.initials: M
authors.lastname: Nautiyal
authors.forename: James C
authors.initials: JC
authors.lastname: Rose
authors.forename: Mark C
authors.initials: MC
authors.lastname: Chappell
authors.forename: Debra I
authors.initials: DI
authors.lastname: Diz
mesh_terms: D000809:Angiotensins / Q000378:metabolism; D000818:Animals; D001623:Betamethasone / Q000633:toxicity*; D005260:Female; D015870:Gene Expression; D005938:Glucocorticoids / Q000633:toxicity*; D008297:Male; D008526:Medulla Oblongata / Q000187:drug effects / Q000378:metabolism*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000378:metabolism*; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D012084:Renin-Angiotensin System; D034561:Sheep, Domestic
chemical_list: D000809:Angiotensins; D005938:Glucocorticoids; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D044140:Receptor, Angiotensin, Type 1; D043562:Receptors, G-Protein-Coupled; D001623:Betamethasone
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