Antenatal betamethasone exposure is associated with lower ANG-(1-7) and increased ACE in the CSF of adult sheep.
Antenatal betamethasone (BM) therapy accelerates lung development in preterm infants but may induce early programming events with long-term cardiovascular consequences. To elucidate these events, we developed a model of programming whereby pregnant ewes are administered BM (2 doses of 0.17 mg/kg) or vehicle at the 80th day of gestation and offspring are delivered at term. BM-exposed (BMX) offspring develop elevated blood pressure; decreased baroreflex sensitivity; and alterations in the circulating, renal, and brain renin-angiotensin systems (RAS) by 6 mo of age. We compared components of the choroid plexus fourth ventricle (ChP4) and cerebral spinal fluid (CSF) RAS between control and BMX male offspring at 6 mo of age. In the choroid plexus, high-molecular-weight renin protein and ANG I-intact angiotensinogen were unchanged between BMX and control animals. Angiotensin-converting enzyme 2 (ACE2) activity was threefold higher than either neprilysin (NEP) or angiotensin 1-converting enzyme (ACE) in control and BMX animals. Moreover, all three enzymes were equally enriched by approximately 2.5-fold in ChP4 brush-border membrane preparations. CSF ANG-(1-7) levels were significantly lower in BMX animals (351.8 ± 76.8 vs. 77.5 ± 29.7 fmol/mg; P < 0.05) and ACE activity was significantly higher (6.6 ± 0.5 vs. 8.9 ± 0.5 fmol·min(-1)·ml(-1); P < 0.05), whereas ACE2 and NEP activities were below measurable limits. A thiol-sensitive peptidase contributed to the majority of ANG-(1-7) metabolism in the CSF, with higher activity in BMX animals. We conclude that in utero BM exposure alters CSF but not ChP RAS components, resulting in lower ANG-(1-7) levels in exposed animals.
['Marshall|Allyson C|AC|', 'Shaltout|Hossam A|HA|', 'Pirro|Nancy T|NT|', 'Rose|James C|JC|', 'Diz|Debra I|DI|', 'Chappell|Mark C|MC|']
D000367:Age Factors D000803:Angiotensin I D000085962:Angiotensin-Converting Enzyme 2 D000818:Animals D017704:Baroreflex D001623:Betamethasone D001794:Blood Pressure D002831:Choroid Plexus D015536:Down-Regulation D005260:Female D005865:Gestational Age D005938:Glucocorticoids D006973:Hypertension D008297:Male D015260:Neprilysin D010446:Peptide Fragments D007703:Peptidyl-Dipeptidase A D011247:Pregnancy D011297:Prenatal Exposure Delayed Effects D012084:Renin-Angiotensin System D012756:Sheep D015854:Up-Regulation
sheep choroid plexus cerebral spinal fluid angiotensin peptidases fetal programming