title: Gestational hypertension in atrial natriuretic peptide knockout mice and the developmental origins of salt-sensitivity and cardiac hypertrophy.
abstract: OBJECTIVE
  To determine the effect of gestational hypertension on the developmental origins of blood pressure (BP), altered kidney gene expression, salt-sensitivity and cardiac hypertrophy (CH) in adult offspring.
  
  
  METHODS
  Female mice lacking atrial natriuretic peptide (ANP-/-) were used as a model of gestational hypertension. Heterozygous ANP+/- offspring was bred from crossing either ANP+/+ females with ANP-/- males yielding ANP+/-(WT) offspring, or from ANP-/- females with ANP+/+ males yielding ANP+/-(KO) offspring. Maternal BP during pregnancy was measured using radiotelemetry. At 14weeks of age, offspring BP, gene and protein expression were measured in the kidney with real-time quantitative PCR, receptor binding assay and ELISA.
  
  
  RESULTS
  ANP+/-(KO) offspring exhibited normal BP at 14weeks of age, but displayed significant CH (P<0.001) as compared to ANP+/-(WT) offspring. ANP+/-(KO) offspring exhibited significantly increased gene expression of natriuretic peptide receptor A (NPR-A) (P<0.001) and radioligand binding studies demonstrated significantly reduced NPR-C binding (P=0.01) in the kidney. Treatment with high salt diet increased BP (P<0.01) and caused LV hypertrophy (P<0.001) and interstitial myocardial fibrosis only in ANP+/-(WT) and not ANP+/-(KO) offspring, suggesting gestational hypertension programs the offspring to show resistance to salt-induced hypertension and LV remodeling. Our data demonstrate that altered maternal environments can determine the salt-sensitive phenotype of offspring.
authors: Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON K7L 3N6, Canada; The Kingston Heart Clinic, 460 Princess Street, Kingston, ON K7L 1C2, Canada.
authors: David W J
authors: DW
authors: Armstrong
authors: M Yat
authors: MY
authors: Tse
authors: Perrie F
authors: PF
authors: O'Tierney-Ginn
authors: Philip G
authors: PG
authors: Wong
authors: Nicole M
authors: NM
authors: Ventura
authors: Judy J
authors: JJ
authors: Janzen-Pang
authors: Murray F
authors: MF
authors: Matangi
authors: Amer M
authors: AM
authors: Johri
authors: B Anne
authors: BA
authors: Croy
authors: Michael A
authors: MA
authors: Adams
authors: Stephen C
authors: SC
authors: Pang
mesh_terms: D000818:Animals; D009320:Atrial Natriuretic Factor / Q000172:deficiency / Q000235:genetics*; D006152:Cyclic GMP / Q000378:metabolism; D005260:Female; D047109:Fetal Development; D015870:Gene Expression; D005786:Gene Expression Regulation; D046110:Hypertension, Pregnancy-Induced / Q000235:genetics* / Q000378:metabolism; D017379:Hypertrophy, Left Ventricular / Q000209:etiology* / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000209:etiology* / Q000378:metabolism; D050784:Proto-Oncogene Protein c-ets-1 / Q000235:genetics / Q000378:metabolism; D017461:Receptors, Atrial Natriuretic Factor / Q000235:genetics / Q000378:metabolism; D055049:Salt Tolerance; D012982:Sodium, Dietary / Q000009:adverse effects*; D020257:Ventricular Remodeling; D050880:p300-CBP Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: C494042:Ets1 protein, mouse; D050784:Proto-Oncogene Protein c-ets-1; D012982:Sodium, Dietary; D009320:Atrial Natriuretic Factor; D050880:p300-CBP Transcription Factors; D017461:Receptors, Atrial Natriuretic Factor; D006152:Cyclic GMP
keywords: ANP; B-type natriuretic peptide; BNP; BP; CV; CVD; Cardiac hypertrophy; Developmental origins; EIA; HS; Hypertension; IUGR; LV; NPR-A; NPR-C; NPS; NS; Natriuretic peptides; Nppa; Npr1; Npr3; PDE; RIA; Salt-sensitivity; atrial natriuretic peptide; blood pressure; cardiovascular; cardiovascular disease; eNOS; endothelial nitric oxide synthase; enzyme immunoassay; high salt; intrauterine growth restriction; left ventricle; natriuretic peptide precursor A gene; natriuretic peptide receptor 1 gene; natriuretic peptide receptor 3 gene; natriuretic peptide receptor A; natriuretic peptide receptor C; natriuretic peptide system; normal salt; phosphodiesterase; radioimmunoassay