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,☆☆,,★★

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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. STUDY DESIGN: 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 1α 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. (Am J Obstet Gynecol 1998;178:527-34.)

Section snippets

Animal protocols

All care and procedures were reviewed and approved by the Oregon Health Sciences University Animal Care and Use Committee. Surgery was performed in 11 fetal sheep at 119 to 124 days' gestation as previously described.2, 16 General anesthesia was induced with a diazepam-ketamine mixture, the ewe was intubated, and anesthesia was maintained with 1.5% halothane and 50% nitrous oxide–50% oxygen. Polyvinyl catheters (1.19 mm inner diameter) were placed in the fetal descending aorta and inferior vena

Generation and characterization of chronic anemia in fetal sheep

Chronic anemia was induced in fetal lambs by daily isovolemic hemorrhage over 6.2 ± 0.3 days (range 5 to 8 days). Two groups of tissue were studied, with one set analyzed for RNA and protein expression and the other set analyzed by capillary morphometry. The gestational age, hematocrit, or hemodynamic data did not differ between these two sets and therefore the anemic fetuses are presented as one group (Table I).

. Hemodynamic data in fetuses made chronically anemic

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Comment

The major finding of this study was that in ovine fetuses with chronic anemia ventricular concentrations of HIF-1α protein increased significantly, as did VEGF mRNA and protein. In concert, capillary density in the left ventricle was maintained and was actually greater in the right ventricle as the heart-to-body weight ratio increased. Studies in chronically anemic fetal sheep have demonstrated significant cardiac adaptations including an approximately 30% increase in heart-to-body weight ratio

Acknowledgements

We thank N. Ferrara (Genentech) for the polyclonal antibody raised against recombinant human VEGF.

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    From the Department of Obstetrics and Gynecology and the Congenital Heart Center, Oregon Health Sciences University,a and the Center for Medical Genetics, Departments of Pediatrics and Medicine, Johns Hopkins University School of Medicine.b

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    Supported by grants from the American Heart Association (G.L.S.), National Institutes of Health grants No. R01-HL55338 (G.L.S.) and R01-HL45043 (L.D.), and Multidisciplinary Training Program in Lung Diseases T32-HL07534 (A.Y.Y.). G.L.S. is an Established Investigator of the American Heart Association.

    Reprint requests: Lowell Davis, MD, Department of Obstetrics and Gynecology, OB Research, L458, Oregon Health Sciences University, 3181 S.W. Sam Jackson Park Road, Portland, OR 97201-3098.

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