title: Cardiac hypertrophy in chronically anemic fetal sheep: Increased vascularization is associated with increased myocardial expression of vascular endothelial growth factor and hypoxia-inducible factor 1.
abstract: OBJECTIVE
  Our purpose was to determine whether the increase in fetal cardiac mass and cardiac output in chronic anemia is accompanied by changes in capillary density or size or changes in levels of vascular endothelial growth factor and hypoxia-inducible factor 1, a basic helix-loop-helix transcription factor that has previously been shown to activate vascular endothelial growth factor gene transcription when cultured cells are subjected to hypoxia.
  
  
  METHODS
  Anemia was induced in near-term ovine fetuses by daily isovolemic hemorrhage. In five fetuses the heart was arrested in diastole, isolated, and fixed at physiologic pressures with adenosine-paraformaldehyde, and morphometric measurements of capillaries were made. In six fetuses cardiac expression of vascular endothelial growth factor and hypoxia-inducible factor 1 protein was detected by Western analysis and vascular endothelial growth factor messenger ribonucleic acid by Northern blot analysis. Eleven age-matched fetuses served as controls.
  
  
  RESULTS
  The anemic fetuses compared with controls had a lower hematocrit (14.8% +/- 0.7% vs 35.3% +/- 1.5%) and a greater heart-to-body weight ratio (10.5 +/- 1.1 vs 7.7 +/- 0.5 gm/kg). The minimal capillary diameter was increased and the intercapillary distance was decreased in both right and left ventricles of anemic fetuses compared with controls. Vascular endothelial growth factor protein was increased 4.5-fold, vascular endothelial growth factor messenger ribonucleic acid 3.2-fold, and hypoxia-inducible factor 1alpha protein 3.8-fold in ventricular tissue from anemic fetuses.
  
  
  CONCLUSIONS
  In chronic fetal anemia cardiac hypertrophy is accompanied by anatomic changes in myocardial capillary morphometry along with induction of hypoxia-inducible factor 1 and vascular endothelial growth factor. These results provide evidence for a pathway by which anemia-hypoxia may stimulate myocardial vascularization.
authors.affiliation: Department of Obstetrics and Gynecology and the Congenital Heart Center, Oregon Health Sciences University, Portland 97201-3098, USA.
authors.forename: C
authors.initials: C
authors.lastname: Martin
authors.forename: A Y
authors.initials: AY
authors.lastname: Yu
authors.forename: B H
authors.initials: BH
authors.lastname: Jiang
authors.forename: L
authors.initials: L
authors.lastname: Davis
authors.forename: D
authors.initials: D
authors.lastname: Kimberly
authors.forename: A R
authors.initials: AR
authors.lastname: Hohimer
authors.forename: G L
authors.initials: GL
authors.lastname: Semenza
mesh_terms: D000740:Anemia / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D000818:Animals; D002196:Capillaries / Q000473:pathology; D002302:Cardiac Output / Q000502:physiology; D006332:Cardiomegaly / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D002478:Cells, Cultured; D002908:Chronic Disease; D003326:Coronary Circulation / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D016228:Endothelial Growth Factors / Q000378:metabolism*; D005260:Female; D005315:Fetal Diseases / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D018257:Helix-Loop-Helix Motifs; D006801:Humans; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008222:Lymphokines / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D012756:Sheep; D014157:Transcription Factors / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
chemical_list: D004268:DNA-Binding Proteins; D016228:Endothelial Growth Factors; C497442:HIF1A protein, human; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008222:Lymphokines; D009687:Nuclear Proteins; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors