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

A. Tintu, E. Rouwet, S. Verlohren, J. Brinkmann, S. Ahmad, F. Crispi, M. van Bilsen, P. Carmeliet, A.C. Staff, M. Tjwa, I. Cetin, E. Gratacos, E. Hernandez Andrade, L. Hofstra, M.J. Jacobs, W.H. Lamers, I. Morano, E. Safak, A. Ahmed, F. le Noble

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    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 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.
    Original languageEnglish
    Article numbere5155
    JournalPLOS ONE
    Volume4
    Issue number4
    DOIs
    Publication statusPublished - 1 Jan 2009

    Cite this

    Tintu, A., Rouwet, E., Verlohren, S., Brinkmann, J., Ahmad, S., Crispi, F., ... le Noble, F. (2009). Hypoxia induces dilated cardiomyopathy in the chick embryo: mechanism, intervention, and long-term consequences. PLOS ONE, 4(4), [e5155]. https://doi.org/10.1371/journal.pone.0005155
    Tintu, A. ; Rouwet, E. ; Verlohren, S. ; Brinkmann, J. ; Ahmad, S. ; Crispi, F. ; van Bilsen, M. ; Carmeliet, P. ; Staff, A.C. ; Tjwa, M. ; Cetin, I. ; Gratacos, E. ; Hernandez Andrade, E. ; Hofstra, L. ; Jacobs, M.J. ; Lamers, W.H. ; Morano, I. ; Safak, E. ; Ahmed, A. ; le Noble, F. / Hypoxia induces dilated cardiomyopathy in the chick embryo: mechanism, intervention, and long-term consequences. In: PLOS ONE. 2009 ; Vol. 4, No. 4.
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    title = "Hypoxia induces dilated cardiomyopathy in the chick embryo: mechanism, intervention, and long-term consequences",
    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 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.",
    author = "A. Tintu and E. Rouwet and S. Verlohren and J. Brinkmann and S. Ahmad and F. Crispi and {van Bilsen}, M. and P. Carmeliet and A.C. Staff and M. Tjwa and I. Cetin and E. Gratacos and {Hernandez Andrade}, E. and L. Hofstra and M.J. Jacobs and W.H. Lamers and I. Morano and E. Safak and A. Ahmed and {le Noble}, F.",
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    Tintu, A, Rouwet, E, Verlohren, S, Brinkmann, J, Ahmad, S, Crispi, F, van Bilsen, M, Carmeliet, P, Staff, AC, Tjwa, M, Cetin, I, Gratacos, E, Hernandez Andrade, E, Hofstra, L, Jacobs, MJ, Lamers, WH, Morano, I, Safak, E, Ahmed, A & le Noble, F 2009, 'Hypoxia induces dilated cardiomyopathy in the chick embryo: mechanism, intervention, and long-term consequences', PLOS ONE, vol. 4, no. 4, e5155. https://doi.org/10.1371/journal.pone.0005155

    Hypoxia induces dilated cardiomyopathy in the chick embryo: mechanism, intervention, and long-term consequences. / Tintu, A.; Rouwet, E.; Verlohren, S.; Brinkmann, J.; Ahmad, S.; Crispi, F.; van Bilsen, M.; Carmeliet, P.; Staff, A.C.; Tjwa, M.; Cetin, I.; Gratacos, E.; Hernandez Andrade, E.; Hofstra, L.; Jacobs, M.J.; Lamers, W.H.; Morano, I.; Safak, E.; Ahmed, A.; le Noble, F.

    In: PLOS ONE, Vol. 4, No. 4, e5155, 01.01.2009.

    Research output: Contribution to journalArticleAcademicpeer-review

    TY - JOUR

    T1 - Hypoxia induces dilated cardiomyopathy in the chick embryo: mechanism, intervention, and long-term consequences

    AU - Tintu, A.

    AU - Rouwet, E.

    AU - Verlohren, S.

    AU - Brinkmann, J.

    AU - Ahmad, S.

    AU - Crispi, F.

    AU - van Bilsen, M.

    AU - Carmeliet, P.

    AU - Staff, A.C.

    AU - Tjwa, M.

    AU - Cetin, I.

    AU - Gratacos, E.

    AU - Hernandez Andrade, E.

    AU - Hofstra, L.

    AU - Jacobs, M.J.

    AU - Lamers, W.H.

    AU - Morano, I.

    AU - Safak, E.

    AU - Ahmed, A.

    AU - le Noble, F.

    PY - 2009/1/1

    Y1 - 2009/1/1

    N2 - 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.

    AB - 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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    DO - 10.1371/journal.pone.0005155

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    JO - PLOS ONE

    JF - PLOS ONE

    SN - 1932-6203

    IS - 4

    M1 - e5155

    ER -