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

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 and le Noble, Ferdinand (2009). Hypoxia induces dilated cardiomyopathy in the chick embryo:mechanism, intervention, and long-term consequences. PLoS ONE, 4 (4),

Abstract

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 rhVEGF165 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.

Publication DOI: https://doi.org/10.1371/journal.pone.0005155
Divisions: Life & Health Sciences > Biosciences
Life & Health Sciences
Aston Medical School
Additional Information: Copyright: © 2009 Tintu et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Uncontrolled Keywords: Agricultural and Biological Sciences(all),Biochemistry, Genetics and Molecular Biology(all),Medicine(all)
Full Text Link: http://www.plos ... al.pone.0005155
Related URLs: http://www.scop ... tnerID=8YFLogxK (Scopus URL)
Published Date: 2009-04-09
Authors: Tintu, Andrei
Rouwet, Ellen
Verlohren, Stefan
Brinkmann, Joep
Ahmad, Shakil ( 0000-0002-9294-0475)
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

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