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Hypoxia induces dilated cardiomyopathy in the chick embryo: mechanism, intervention, and long-term consequences
Andrei Tintu1, Ellen Rouwet, Stefan Verlohren
1Laboratory for Angiogenesis and Cardiovascular Pathology, Max-Delbrueck-Center for Molecular Medicine, Berlin, Germany.
Insights
In utero hypoxia causes lasting heart disease in chick embryos, leading to cardiomyopathy and reduced cardiac function. Vascular Endothelial Growth Factor (VEGF) plays a key role in this process.
Area of Science:
- Cardiovascular Development
- Developmental Biology
- Fetal Programming
Background:
- Intrauterine growth restriction (IUGR) is linked to future cardiovascular disease risk.
- In utero hypoxia is a common cause of IUGR and impacts fetal development.
- Previous studies demonstrated chronic hypoxia alters cardiovascular development in chick embryos.
Purpose of the Study:
- To characterize cardiac disease in chick embryos exposed to hypoxia.
- To investigate the role of vascular endothelial growth factor (VEGF) in hypoxia-induced cardiomyopathy.
Main Methods:
- Chick embryos were exposed to hypoxia and cardiac structure/function assessed via histology, echocardiography, and ex vivo contractility measurements.
- Vascular Endothelial Growth Factor (VEGF) and soluble VEGF receptor-1 (sFlt-1) were administered to investigate VEGF's role.
- Cardiac assessments were performed at embryonic day 20 (E20) and adulthood.
Main Results:
- Hypoxic chick embryos exhibited cardiomyopathy with left ventricular (LV) dilatation, reduced wall mass, and increased apoptosis.
- Hypoxic hearts showed impaired pump function (decreased LV ejection fraction) and diastolic dysfunction.
- VEGF administration worsened cardiac phenotype, while sFlt-1 administration normalized it in hypoxic embryos.
Conclusions:
- Hypoxia induces cardiomyopathy and decreased cardiac performance in chick embryos, with a significant VEGF-mediated component.
- This hypoxia-induced cardiac dysfunction persists into adulthood.
- VEGF signaling is a critical mediator of cardiac development under hypoxic conditions.
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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