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.

Sex-specific programming of hypertension in offspring of late-gestation diabetic rats.

BACKGROUND: The intrauterine environment strongly influences adult disease susceptibility. We used a rat model of third-trimester maternal diabetes to test the hypothesis that adult offspring exposed to hyperglycemia in utero display increased blood pressure and alterations in vascular responsiveness. METHODS: Diabetes was induced by streptozotocin injection to pregnant rats on gestation day 13 (term 21 d) and partially controlled with insulin injections. Hemodynamic function was evaluated in 6-12-mo-old offspring. RESULTS: Male but not female offspring of diabetic mothers (ODM) had significantly increased blood pressure as compared with controls; heart rate (HR) was similar. For both sexes, HR baroreflex responses were similar as were in vivo hemodynamic responses to angiotensin II, nitric oxide synthase inhibition, and ganglionic blockade. Aortic contractility to angiotensin II was similar in the two groups. Nitric oxide synthase inhibition and the Cu/Zn superoxide dismutase inhibitor diethyldithiocarbamate, but not the superoxide dismutase-mimetic Tempol, significantly increased contractile responses to angiotensin II in controls but not ODM. Reduced nicotinamide adenine dinucleotide phosphate-stimulated superoxide production was greater in male ODM than in controls (P < 0.05). CONCLUSION: Exposure to hyperglycemia in utero results in sex-specific cardiovascular changes in adult offspring. Impaired nitric oxide-reactive oxygen species signaling may play a significant role in the hemodynamic phenotype of ODM.