Hypoxia induces dilated cardiomyopathy in the chick embryo: mechanism, intervention, and long-term consequences.

Publisher: Public Library of Science Country of Publication: United States NLM ID: 101285081 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1932-6203 (Electronic) Linking ISSN: 19326203 NLM ISO Abbreviation: PLoS One Subsets: MEDLINE

Original Publication: San Francisco, CA : Public Library of Science

Cardiomyopathy, Dilated*/etiology ; Cardiomyopathy, Dilated*/physiopathology ; Cardiomyopathy, Dilated*/therapy ; Heart*/anatomy & histology ; Heart*/embryology ; Hypoxia*/complications ; Hypoxia*/physiopathology; Heart Defects, Congenital/*etiology; Animals ; Apoptosis ; Chick Embryo/anatomy & histology ; Chick Embryo/drug effects ; Chick Embryo/metabolism ; Chickens ; Connectin ; Echocardiography ; Fetal Growth Retardation/etiology ; Fetal Growth Retardation/physiopathology ; Humans ; Muscle Proteins/metabolism ; Myocardial Contraction/physiology ; Myocytes, Cardiac/metabolism ; Myocytes, Cardiac/ultrastructure ; Protein Kinases/metabolism ; Vascular Endothelial Growth Factor A/pharmacology ; Vascular Endothelial Growth Factor Receptor-1/metabolism ; Ventricular Function, Left

Background: Intrauterine growth restriction is associated with an increased future risk for developing cardiovascular diseases. Hypoxia in utero is a common clinical cause of fetal growth restriction. We have previously shown that chronic hypoxia alters cardiovascular development in chick embryos. The aim of this study was to further characterize cardiac disease in hypoxic chick embryos.
Methods: Chick embryos were exposed to hypoxia and cardiac structure was examined by histological methods one day prior to hatching (E20) and at adulthood. Cardiac function was assessed in vivo by echocardiography and ex vivo by contractility measurements in isolated heart muscle bundles and isolated cardiomyocytes. Chick embryos were exposed to vascular endothelial growth factor (VEGF) and its scavenger soluble VEGF receptor-1 (sFlt-1) to investigate the potential role of this hypoxia-regulated cytokine.
Principal Findings: Growth restricted hypoxic chick embryos showed cardiomyopathy as evidenced by left ventricular (LV) dilatation, reduced ventricular wall mass and increased apoptosis. Hypoxic hearts displayed pump dysfunction with decreased LV ejection fractions, accompanied by signs of diastolic dysfunction. Cardiomyopathy caused by hypoxia persisted into adulthood. Hypoxic embryonic hearts showed increases in VEGF expression. Systemic administration of rhVEGF(165) to normoxic chick embryos resulted in LV dilatation and a dose-dependent loss of LV wall mass. Lowering VEGF levels in hypoxic embryonic chick hearts by systemic administration of sFlt-1 yielded an almost complete normalization of the phenotype.
Conclusions/significance: Our data show that hypoxia causes a decreased cardiac performance and cardiomyopathy in chick embryos, involving a significant VEGF-mediated component. This cardiomyopathy persists into adulthood.

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G0601295 United Kingdom MRC_ Medical Research Council; RG/09/001/25940 United Kingdom BHF_ British Heart Foundation

0 (Connectin)
0 (Muscle Proteins)
0 (TTN protein, human)
0 (VEGFA protein, human)
0 (Vascular Endothelial Growth Factor A)
EC 2.7.- (Protein Kinases)
EC 2.7.10.1 (Vascular Endothelial Growth Factor Receptor-1)

Date Created: 20090410 Date Completed: 20091027 Latest Revision: 20211028

20240513

PMC2663815

10.1371/journal.pone.0005155

19357774