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

• Published in: PloS one 2009-04, Vol.4 (4), p.e5155-e5155
• Main Authors: Tintu, Andrei, Rouwet, Ellen, Verlohren, Stefan, Brinkmann, Joep, Ahmad, Shakil, Crispi, Fatima, van Bilsen, Marc, Carmeliet, Peter, Staff, Anne Cathrine, Tjwa, Marc, Cetin, Irene, Gratacos, Eduard, Hernandez-Andrade, Edgar, Hofstra, Leo, Jacobs, Michael, Lamers, Wouter H, Morano, Ingo, Safak, Erdal, Ahmed, Asif, le Noble, Ferdinand
• Format: Article
• Language: English
• Subjects: Angiogenesis; Animals; Anoxemia; Anoxèmia; Apoptosis; Biomedical research; Cardiac muscle; Cardiology; Cardiomyocytes; Cardiomyopathy; Cardiomyopathy, Dilated - etiology; Cardiomyopathy, Dilated - physiopathology; Cardiomyopathy, Dilated - therapy; Cardiovascular diseases; Cardiovascular Disorders/Heart Failure; Chick Embryo - anatomy & histology; Chick Embryo - drug effects; Chick Embryo - metabolism; Chickens; Connectin; Cor; Coronary artery disease; Coronary diseases; Creixement fetal; Development and progression; Developmental Biology/Developmental Molecular Mechanisms; Developmental Biology/Embryology; Diagnosis; Dilated cardiomyopathy; Echocardiography; Embryonic development; Embryos; Fetal development; Fetal growth; Fetal Growth Retardation - etiology; Fetal Growth Retardation - physiopathology; Fetuses; Gynecology; Hatching; Health risks; Heart; Heart - anatomy & histology; Heart - embryology; Heart Defects, Congenital - etiology; Heart diseases; Hospitals; Humans; Hypoxia; Hypoxia - complications; Hypoxia - physiopathology; Laboratories; Malalties coronàries; Medical research; Medicine; Muscle contraction; Muscle Proteins - metabolism; Myocardial Contraction - physiology; Myocardial diseases; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - ultrastructure; Obstetrics; Pathology; Physiology; Protein Kinases - metabolism; Proteins; Rodents; Surgery; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - pharmacology; Vascular Endothelial Growth Factor Receptor-1 - metabolism; Ventricle; Ventricular Function, Left
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0005155

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. 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. 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. 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.