Angiotensin II–induced cardiovascular load regulates cardiac remodeling and related gene expression in late-gestation fetal sheep

Background: Angiotensin II (ANG II) stimulates fetal heart growth, although little is known regarding changes in cardiomyocyte endowment or the molecular pathways mediating the response. We measured cardiomyocyte proliferation and morphology in ANG II–treated fetal sheep and assessed transcriptional pathway responses in ANG II and losartan (an ANG II type 1 receptor antagonist) treated fetuses. Methods: In twin-gestation pregnant sheep, one fetus received ANG II (50 μg/kg/min i.v.) or losartan (20 mg/kg/d i.v.) for 7 d; noninstrumented twins served as controls. Results: ANG II produced increases in heart mass, cardiomyocyte area (left ventricle (LV) and right ventricle mononucleated and LV binucleated cells), and the percentage of Ki-67–positive mononucleated cells in the LV (all P < 0.05). ANG II and losartan produced generally opposing changes in gene expression, affecting an estimated 55% of the represented transcriptome. The most prominent significantly affected biological pathways included those involved in cytoskeletal remodeling and cell cycle activity. Conclusion: ANG II produces an increase in fetal cardiac mass via cardiomyocyte hypertrophy and likely hyperplasia, involving transcriptional responses in cytoskeletal remodeling and cell cycle pathways.